US5798354A - Use of adamantyl-substituted polycyclic acetylene compounds in skin and hair treatment - Google Patents

Use of adamantyl-substituted polycyclic acetylene compounds in skin and hair treatment Download PDF

Info

Publication number
US5798354A
US5798354A US08/678,416 US67841696A US5798354A US 5798354 A US5798354 A US 5798354A US 67841696 A US67841696 A US 67841696A US 5798354 A US5798354 A US 5798354A
Authority
US
United States
Prior art keywords
adamantyl
radical
benzoic acid
formula
substituted polycyclic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US08/678,416
Inventor
Jean-Michel Bernardon
Bruno Charpentier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Galderma Research and Development SNC
Original Assignee
Centre International de Recherches Dermatologiques Galderma
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Centre International de Recherches Dermatologiques Galderma filed Critical Centre International de Recherches Dermatologiques Galderma
Priority to US08/678,416 priority Critical patent/US5798354A/en
Application granted granted Critical
Publication of US5798354A publication Critical patent/US5798354A/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/347—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4986—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with sulfur as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/30—Compounds having groups
    • C07C43/315—Compounds having groups containing oxygen atoms singly bound to carbon atoms not being acetal carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/56—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups
    • C07C47/57—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/19—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups having unsaturation outside the aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
    • C07C65/26—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/28—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups having unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/007—Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/14—Acetic acid esters of monohydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/22—Radicals substituted by singly bound oxygen or sulfur atoms etherified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to novel adamantyl-substituted polycyclic acetylene compounds and to pharmaceutical/cosmetic compositions comprised thereof; the subject compounds are especially useful in human or veterinary medicine, or, alternatively, in cosmetic compositions.
  • the compounds according to the invention display marked activity in the fields of cell differentiation and proliferation and are particularly useful in the topical and systemic treatment of dermatological conditions associated with a keratinization disorder, dermatological conditions (and the like) including an inflammatory and/or immunoallergic component, and dermal or epidermal proliferations, whether benign or malignant.
  • the subject compounds can, in addition, be used for the treatment of degenerative diseases of the connective tissue, for controlling aging of the skin, whether photoinduced or chronological, and for treating healing disorders.
  • they are also useful for ophthalmological applications, especially for the treatment of corneopathies.
  • the compounds of this invention are also useful for the treatment of osteoporosis or for the treatment of viral diseases, as well as for the treatment of any condition related to a hypervitaminosis A. Generally, they are useful for the treatment of any disease state which is associated with a modification in the expression of receptors belonging to the superfamily of receptors for steroidal and thyroid hormones.
  • the compounds according to this invention can also be formulated into cosmetic compositions for body and hair care/hygiene.
  • the polycyclic acetylene compounds according to this invention have the following structural formula (I): ##STR3## in which X is a hydrogen atom or a halogen atom; R 1 is a hydrogen atom, a --CH 3 radical, a --CH 2 --O--R 4 radical, a --CH 2 --O--CO--R 5 radical, an --O--R 6 radical, an --O.paren open-st.CH 2 .paren close-st. m .paren open-st.CO.paren close-st. n R 7 radical, a .paren open-st.CH 2 .paren close-st.
  • Ar is a radical selected from among those of the following formulae (a)-(f): ##STR4## wherein R 10 and R 11 are as defined below;
  • R 2 is a hydrogen atom or a halogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, an --O--CH 2 --O--CH 2 --CH 2 --O--CH 3 radical or an --O--R 13 radical, wherein R 13 is as defined below;
  • R 3 is an --O--CH 2 --O--CH 2 --CH 2 --O--CH 3 radical, a .paren open-st.Y.paren close-st.
  • R 14 radical, wherein m, n, q and t and the Y and R 14 radicals are as defined below; m is an integer equal to 1, 2 or 3, n is an integer equal to 0 or 1, p is an integer equal to 0, 1, 2 or 3, q is an integer ranging from 0 to 12, inclusive, and t is an integer ranging from 0 to 10, inclusive; R 4 is a hydrogen atom or a lower alkyl radical; R 5 is a lower alkyl radical; R 6 is a hydrogen atom or a lower alkyl radical; R 7 is a lower alkyl radical or a heterocycle; R 8 is a hydrogen atom, a lower alkyl radical, or a radical: ##STR5## in which R' and R", which may be identical or different, are each a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino acid or peptide or sugar residue, with the proviso that
  • n .paren open-st.CH 2 .paren close-st.R 14 , a hydroxyl radical, an --O--R 12 radical or an --O--COR 12 radical; and Y is an oxygen or sulfur atom or an --S(O) p radical.
  • This invention also features the salts of the compounds of formula (I) in the event that the R 1 radical or R 14 radical represents a carboxylic acid functional group or a sulfonic acid functional group, or, alternatively, when the R 14 radical represents an amine functional group, as well as the chiral (optical) and geometric isomers thereof.
  • the compounds according to the invention exist in the form of salts, they are preferably salts of an alkali metal or alkaline earth metal, or, alternatively, of zinc or of an organic amine.
  • FIGS. 1 and 2 set forth reaction schemes/mechanisms illustrating representative syntheses for the preparation of the polycyclic acetylene compounds according to the present invention.
  • lower alkyl radical is intended an alkyl radical having from 1 to 6 carbon atoms and preferably the methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl radicals.
  • linear or branched alkyl radical having from 1 to 20 carbon atoms is preferably intended methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl radicals.
  • radical a radical preferably having 2 or 3 carbon atoms, especially a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.
  • polyhydroxyalkyl radical is intended a radical preferably having from 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl or 2,3,4,5-tetrahydroxypentyl radicals, or the pentaerythritol residue.
  • aryl radical is preferably intended a phenyl radical optionally substituted by at least one halogen atom, or a hydroxyl or nitro functional group.
  • aralkyl radical is preferably intended a benzyl or phenethyl radical optionally substituted by at least one halogen atom, or a hydroxyl or nitro functional group.
  • alkenyl radical is intended a radical preferably having from 2 to 5 carbon atoms and one or more sites of ethylenic unsaturation, such as, more particularly, the allyl radical.
  • alkynyl radical is preferably intended a radical having from 2 to 6 carbon atoms and at least one site of acetylenic unsaturation, such as the propargyl radical.
  • sugar residue is intended a residue derived especially from glucose, galactose or mannose, or alternatively from glucuronic acid.
  • amino acid residue is especially intended a residue derived from lysine, glycine or aspartic acid, and by “peptide residue” is more particularly intended a dipeptide or tripeptide residue prepared via the combination of amino acids.
  • heterocycle is preferably intended a piperidino, morpholino, pyrrolidino or piperazino radical, optionally substituted in the 4-position by a C 1 -C 6 alkyl or mono- or polyhydroxyalkyl radical, as defined above.
  • R 2 and R 11 radicals are halogen atoms, they are preferably fluorine, chlorine or bromine atoms.
  • the more particularly preferred compounds of formula (I) are those in which at least one, and preferably all, of the conditions given below are satisfied:
  • R 1 is a --(CH 2 ) p --CO--R 8 radical
  • R 3 is an --O--CH 2 --O--CH 2 --CH 2 --O--CH 3 or .paren open-st.Y.paren close-st. n .paren open-st.CH 2 .paren close-st. q R 14 radical;
  • Ar is a radical selected from among those of formulae (a) and (e);
  • R 2 is a linear or branched alkyl radical having from 1 to 20 carbon atoms or, alternatively, an --O--R 13 radical.
  • the present invention also features the processes for the preparation of the compounds of formula (I), in particular via the reaction schemes illustrated in FIGS. 1 and 2.
  • the compounds of formula I(a) can be prepared (FIG. 1) from the acetylene derivative (4) by conversion into a lithium and then zinc derivative (5). Such derivative is then coupled with the halogenated derivative (6) (preferably the iodinated or brominated derivative) in the presence of a palladium catalyst (preferably tetrakis(triphenylphosphine)palladium(0)) in a solvent such as THF.
  • a palladium catalyst preferably tetrakis(triphenylphosphine)palladium(0)
  • the acetylene derivative (4) can, in its turn, be obtained from the brominated derivative (1) via three different techniques:
  • R 1 , R 2 and R 3 are as defined above in respect of the compounds of formula (I) or are derivatives thereof which are suitably protected as to be compatible with the coupling conditions.
  • the latter when they represent the hydroxyl radical, the latter is preferably protected in the tert-butyldimethylsilyloxy or methoxyethoxymethoxy form. Deprotection is then carried out either in the presence of tetrabutylammonium fluoride or trimethylsilyl iodide or in acidic medium (for example HCl).
  • R 3 is a .paren open-st.CH 2 .paren close-st. q CO--R 8 radical or a --CH ⁇ CH--(CH 2 ) t --R 14 radical
  • the compounds are preferably prepared from the phenol derivative (9) according to the reaction scheme illustrated in FIG. 2, namely, conversion of the phenol derivative (9) into the triflate (10) and then nucleophilic substitution in the presence of a palladium catalyst (for example tetrakis(triphenylphosphine)palladium(0)) according to the general conditions described in S. Cacchi et al, Tetrahedron Letters, 27, 3931-4 (1986) or in W. J. Scott et al, J. Org. Chem., 50, 2302-8 (1985).
  • a palladium catalyst for example tetrakis(triphenylphosphine)palladium(0)
  • the present invention also features therapeutic/pharmaceutical applications of the compounds of formula (I).
  • these compounds exhibit either an agonist activity in the test for differentiation of embryonic teratocarcinoma cells (F9) in mice (Cancer Research, 43, p. 5268 (1983)) and/or in the test for inhibition of ornithine decarboxylase after induction by TPA in mice (Cancer Research, 38, p. 793-801 (1978)) or, in contrast, an antagonist activity with respect to the expression of one or more biological markers in the test for differentiation of embryonic teratocarcinoma cells (F9) in mice (Skin Pharmacol., 3, pp. 256-267 (1990)) and/or for the in vitro differentiation of human keratinocytes (Anal. Biochem., 192, pp. 232-236 (1991)).
  • a keratinization disorder manifesting an inflammatory and/or immunoallergic component and, in particular, all forms of psoriasis, whether cutaneous, mucosal or ungual, and even psoriatic rheumatism, or alternatively cutaneous or skin atopy, such as eczema, or respiratory atopy or alternatively gingival hypertrophy; the compounds can also be used in certain inflammatory conditions not exhibiting keratinization disorder,
  • the compounds according to the invention can advantageously be used in combination with other compounds displaying a retinoid-type activity, with vitamins D or derivatives thereof, with corticosteroids, with compounds which control free radicals, ⁇ -hydroxy or ⁇ -keto acids or derivatives thereof, or alternatively with ion channel blockers.
  • vitamins D or derivatives thereof are intended, for example, derivatives of vitamin D 2 or D 3 and in particular 1,25-dihydroxyvitamin D 3 .
  • compounds which control free radicals are intended, for example, ⁇ -tocopherol, superoxide dismutase, ubiquinol or certain metal chelating agents.
  • ⁇ -hydroxy or ⁇ -keto acids or derivatives thereof are intended, for example, lactic, malic, citric, glycolic, mandelic, tartaric, glyceric or ascorbic acids or salts, amides or esters thereof.
  • ion channel blockers are intended, for example, minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) and derivatives thereof.
  • the present invention thus also features medicinal compositions containing at least one compound of formula (I), one of its chiral or geometric isomers, or one of its pharmaceutically accepetable salts, or other derivatives thereof.
  • the administration of the compounds according to the invention can be carried out systemically, enterally, parenterally, topically or ocularly.
  • the medicinal/pharmaceutical compositions may be in the form of tablets, hard gelatin capsules, dragees, syrups, suspensions, solutions, elixirs, powders, granules, emulsions or polymeric or lipid microspheres or nanospheres or vesicles which permit a controlled release.
  • the compositions may be in the form of solutions or suspensions for perfusion or for injection.
  • the compounds according to the invention are generally administered at a daily dose of approximately 0.01 mg/kg to 100 mg/kg by body weight, and this at the rate or regime of 1 to 3 doses per diem.
  • compositions based on compounds according to the invention are more particularly intended for treating the skin and the mucosal membranes and can then be provided in the form of ointments, creams, milks, salves, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They can also be provided in the form of polymeric or lipid vesicles or nanospheres or microspheres or of polymeric patches and of hydrogels which permit controlled release. These compositions for topical administration can, moreover, be provided either in anhydrous form or in an aqueous form, according to the particular clinical indication.
  • compositions for a topical or ocular application contain at least one compound of formula (I), or one of its optical or geometric isomers or, alternatively one of its salts, etc., at a concentration preferably ranging from 0.001% to 5% by weight relative to the total weight of the composition.
  • the compounds of formula (I) according to the invention also find application in the cosmetics field, in particular for body and hair care/hygiene, and especially for the treatment of skins tending to develop acne, for hair regrowth and combating hair loss, for combating the greasy appearance of the skin or the hair, for protecting against the deleterious effects of sunlight or in the treatment of physiologically dry skin, and for preventing and/or for controlling photoinduced or chronologic aging.
  • the compounds according to the invention can, moreover, be advantageously be used in combination with other compounds displaying a retinoid-type activity, with vitamins D or derivatives thereof, with corticosteroids, with compounds which control free radicals, with ⁇ -hydroxy or ⁇ -keto acids or derivatives thereof, or alternatively with ion channel blockers, all of these various active agents being as defined above.
  • the present invention therefore also features cosmetic compositions comprising a cosmetically acceptable vehicle, carrier or diluent which is suitable for topical application, at least one compound of formula (I) or one of its chiral or geometric isomers, or one of its salts, etc.
  • Such cosmetic compositions are advantageously in the form of a cream, milk, lotion, ointment, gel, polymeric or lipid vesicles or nanospheres or microspheres, soap or shampoo.
  • the concentration of the compound of formula (I) in the cosmetic compositions according to the invention advantageously ranges from 0.001% and 3% by weight relative to the total weight of the composition.
  • the medicinal and cosmetic compositions according to the invention can, in addition, contain inert or even pharmacodynamically or cosmetically active additives or combinations of these additives, and, especially: wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients; hydrating or moisturizing agents such as glycerol, PEG 400, thiamorpholinone and its derivatives or alternatively urea; anti-seborrhoeic or anti-acne agents such as S-carboxymethylcysteine, S-benzylcysteamine, their salts or derivatives thereof, or benzoyl peroxide; antibiotics such as erythromycin and esters thereof, neomycin, clindamycin and esters thereof, or tetracyclines; anti-fungal agents such as ketoconazole or 4,5-polymethylene-3-isothiazolidones; agents promoting hair regrowth, such
  • compositions according to the invention can also contain flavor-enhancing agents, preservatives such as the esters of para-hydroxybenzoic acid, stabilizing agents, moisture-regulating agents, pH-regulating agents, osmotic-pressure-modifying agents, emulsifying agents, UV-A and UV-B screening agents and antioxidants such as ⁇ -tocopherol, butylated hydroxyanisole or butylated hydroxytoluene.
  • the solution was treated with 4.8 ml (33 mmol) of diethyl chlorophosphate and the temperature was permitted to return to room temperature.
  • This solution was transferred to a lithium diisopropylamide solution which had been prepared using 9.35 ml (66 mmol) of diisopropylamine and 41 ml (66 mmol) of n-butyllithium (1.6M in hexane) in 90 ml of THF at -78° C. The temperature was permitted to return to room temperature and the mixture was stirred for twelve hours.
  • reaction mixture was poured into ice-cold water and the pH was adjusted to 1 with hydrochloric acid (5N). Extraction was carried out with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
  • the compound obtained in part (a) above (28.5 g, 72 mmol) was dissolved in 200 ml of THF. The solution obtained was added dropwise over magnesium (2.4 g, 100 mmol) and iodine crystals. After introduction, heating was carried out at reflux for two hours, cooling was carried out to -78° C. and a stream of CO 2 was charged therein for one hour.
  • reaction mixture is poured into a saturated aqueous ammonium chloride solution and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
  • reaction mixture was stirred at room temperature for one hour, was poured into water and was extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
  • reaction mixture was stirred for thirty minutes, 75 ⁇ l (1.2 mmol) of iodomethane were then added and the reaction mixture was stirred at room temperature for four hours.
  • the reaction mixture was then poured into water and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
  • Example 8(b) In a manner analogous to Example 8(b), from 900 mg (1.9 mmol) of the preceding methyl ester, 700 mg (80%) of 4- 3-(1-adamantyl)-4-hexyloxyphenylethynyl!-benzoic acid were obtained, which acid had the melting point 260°-2° C.
  • reaction mixture was poured into ice-cold water and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
  • Example 8(b) In a manner analogous to Example 8(b), from 1.5 g (3.1 mmol) of the preceding methyl ester, 1.4 g (95%) of the expected acid was obtained, which acid had the melting point 204°-5° C.
  • Example 12(d) In a manner analogous to Example 12(d), from 5.5 g (9.1 mmol) of the preceding product, 900 mg (23%) of the expected acetylene derivative were obtained in the form of a colorless oil.
  • Example 12(d) In a manner analogous to Example 12(d), from 2 g (3.8 mmol) of the preceding product, 1.3 g (93%) of the expected acetylene derivative were obtained in the form of a colorless oil.
  • Example 8(b) In a manner analogous to Example 8(b), from 254 mg (0.5 mmol) of the preceding methyl ester, 100 mg (40%) of 4- 3-(1-adamantyl)-4-(5-carbamoylpentyloxy)phenylethynyl!benzoic acid were collected, which acid had the melting point 269°-70° C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Birds (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cosmetics (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Novel pharmaceutically/cosmetically-active adamantyl-substituted polycyclic acetylene compounds have the structural formula (I): ##STR1## wherein Ar is a radical having one of the formulae (a)-(f): ##STR2## and are useful for the treatment of a wide variety of disease states, whether human or veterinary, for example dermatological, rheumatic, respiratory, cardiovascular, bone and ophthalmological disorders, as well as for the treatment of mammalian skin and hair conditions/disorders.

Description

CROSS-REFERENCE TO COMPANION APPLICATIONS
This application is a divisional of application Ser. No. 08/429,045, filed Apr. 26, 1995, now U.S. Pat. No. 5,574,036. Copending applications Ser. No. 08/429,096, Attorney Docket No. 016800-023! and Ser. No. 08/429,492 Attorney Docket No. 016800-024!, both filed concurrently herewith and assigned to the assignee hereof. Cf. copending applications Ser. No. 08/350,913 Attorney Docket No. 016800-006!, Ser. No. 08/357,024 Attorney Docket No. 016800-007! and Ser. No. 08/356,680 Attorney Docket No. 016800-008!, each filed Dec. 15, 1994 and each also assigned to the assignee hereof.
BACKGROUND OF THE INVENTION Technical Field of the Invention
The present invention relates to novel adamantyl-substituted polycyclic acetylene compounds and to pharmaceutical/cosmetic compositions comprised thereof; the subject compounds are especially useful in human or veterinary medicine, or, alternatively, in cosmetic compositions.
SUMMARY OF THE INVENTION
The compounds according to the invention display marked activity in the fields of cell differentiation and proliferation and are particularly useful in the topical and systemic treatment of dermatological conditions associated with a keratinization disorder, dermatological conditions (and the like) including an inflammatory and/or immunoallergic component, and dermal or epidermal proliferations, whether benign or malignant. The subject compounds can, in addition, be used for the treatment of degenerative diseases of the connective tissue, for controlling aging of the skin, whether photoinduced or chronological, and for treating healing disorders. Moreover, they are also useful for ophthalmological applications, especially for the treatment of corneopathies.
The compounds of this invention are also useful for the treatment of osteoporosis or for the treatment of viral diseases, as well as for the treatment of any condition related to a hypervitaminosis A. Generally, they are useful for the treatment of any disease state which is associated with a modification in the expression of receptors belonging to the superfamily of receptors for steroidal and thyroid hormones.
Too, the compounds according to this invention can also be formulated into cosmetic compositions for body and hair care/hygiene.
Briefly, the polycyclic acetylene compounds according to this invention have the following structural formula (I): ##STR3## in which X is a hydrogen atom or a halogen atom; R1 is a hydrogen atom, a --CH3 radical, a --CH2 --O--R4 radical, a --CH2 --O--CO--R5 radical, an --O--R6 radical, an --O.paren open-st.CH2 .paren close-st.m .paren open-st.CO.paren close-st.n R7 radical, a .paren open-st.CH2 .paren close-st.p CO--R8 radical, a .paren open-st.CH2 .paren close-st.p CO--O--R9 radical or an --S(O)p --R10 radical, wherein m, n and p and the radicals R4 to R10 are as defined below; Ar is a radical selected from among those of the following formulae (a)-(f): ##STR4## wherein R10 and R11 are as defined below; R2 is a hydrogen atom or a halogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, an --O--CH2 --O--CH2 --CH2 --O--CH3 radical or an --O--R13 radical, wherein R13 is as defined below; R3 is an --O--CH2 --O--CH2 --CH2 --O--CH3 radical, a .paren open-st.Y.paren close-st.n (--CH2 .paren close-st.q R14 radical, a .paren open-st.CH2 .paren close-st.m Y.paren open-st.CH2 .paren close-st.q R14 radical or a --CH═CH.paren open-st.CH2 .paren close-st.t R14, radical, wherein m, n, q and t and the Y and R14 radicals are as defined below; m is an integer equal to 1, 2 or 3, n is an integer equal to 0 or 1, p is an integer equal to 0, 1, 2 or 3, q is an integer ranging from 0 to 12, inclusive, and t is an integer ranging from 0 to 10, inclusive; R4 is a hydrogen atom or a lower alkyl radical; R5 is a lower alkyl radical; R6 is a hydrogen atom or a lower alkyl radical; R7 is a lower alkyl radical or a heterocycle; R8 is a hydrogen atom, a lower alkyl radical, or a radical: ##STR5## in which R' and R", which may be identical or different, are each a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino acid or peptide or sugar residue, with the proviso that R' and R" may together form, with the nitrogen atom from which they depend, a nitrogen-containing heterocycle; R9 is a hydrogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, an alkenyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl or aralkyl radical, or a sugar residue or an amino acid or peptide residue; R10 is a hydrogen atom or a lower alkyl radical; R11 is a hydrogen atom, a halogen atom, a lower alkyl radical, a hydroxyl radical, or an --O--R12 or --O--COR12 radical, wherein R12 is as defined below; R12 is a lower alkyl radical; R13 is a hydrogen atom or a linear or branched alkyl radical having from 1 to 20 carbon atoms; R14 is a hydrogen atom, a lower alkyl radical, an alkenyl radical, an alkynyl radical, a C3 -C6 cycloaliphatic radical, a mono- or polyhydroxyalkyl radical, said hydroxyls optionally being protected as methoxy, acetoxy or acetonide groups, an aryl or aralkyl radical, a --CO--R8 radical, a --COOR9 radical, an --S(O)p --R10 radical, a radical: ##STR6## or, but only in the event that n is equal to 0 and R3 is .paren open-st.Y.paren close-st.n .paren open-st.CH2 .paren close-st.R14, a hydroxyl radical, an --O--R12 radical or an --O--COR12 radical; and Y is an oxygen or sulfur atom or an --S(O)p radical.
This invention also features the salts of the compounds of formula (I) in the event that the R1 radical or R14 radical represents a carboxylic acid functional group or a sulfonic acid functional group, or, alternatively, when the R14 radical represents an amine functional group, as well as the chiral (optical) and geometric isomers thereof. When the compounds according to the invention exist in the form of salts, they are preferably salts of an alkali metal or alkaline earth metal, or, alternatively, of zinc or of an organic amine.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1 and 2 set forth reaction schemes/mechanisms illustrating representative syntheses for the preparation of the polycyclic acetylene compounds according to the present invention.
DETAILED DESCRIPTION OF BEST MODE AND PREFERRED EMBODIMENTS OF THE INVENTION
More particularly according to the present invention, by "lower alkyl radical" is intended an alkyl radical having from 1 to 6 carbon atoms and preferably the methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl radicals.
By "linear or branched alkyl radical having from 1 to 20 carbon atoms" is preferably intended methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl radicals.
By "monohydroxyalkyl radical" is intended a radical preferably having 2 or 3 carbon atoms, especially a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.
By "polyhydroxyalkyl radical" is intended a radical preferably having from 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl or 2,3,4,5-tetrahydroxypentyl radicals, or the pentaerythritol residue.
By "aryl radical" is preferably intended a phenyl radical optionally substituted by at least one halogen atom, or a hydroxyl or nitro functional group.
By "aralkyl radical" is preferably intended a benzyl or phenethyl radical optionally substituted by at least one halogen atom, or a hydroxyl or nitro functional group.
By "alkenyl radical" is intended a radical preferably having from 2 to 5 carbon atoms and one or more sites of ethylenic unsaturation, such as, more particularly, the allyl radical.
By "alkynyl radical" is preferably intended a radical having from 2 to 6 carbon atoms and at least one site of acetylenic unsaturation, such as the propargyl radical.
By "sugar residue" is intended a residue derived especially from glucose, galactose or mannose, or alternatively from glucuronic acid.
By "amino acid residue" is especially intended a residue derived from lysine, glycine or aspartic acid, and by "peptide residue" is more particularly intended a dipeptide or tripeptide residue prepared via the combination of amino acids.
Lastly, by "heterocycle" is preferably intended a piperidino, morpholino, pyrrolidino or piperazino radical, optionally substituted in the 4-position by a C1 -C6 alkyl or mono- or polyhydroxyalkyl radical, as defined above.
When the X, R2 and R11 radicals are halogen atoms, they are preferably fluorine, chlorine or bromine atoms.
Among the compounds of formula (I) according to the present invention, particularly representative are the following:
4- 3-(1-adamantyl)-4-methoxyphenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-hydroxyphenylethynyl!benzoic acid;
5- 3-(1-Adamantyl)-4-methoxyphenylethynyl!-2-thiophenecarboxylic acid;
5- 3-(1-Adamantyl)-4-hydroxyphenylethynyl!-2-thiophenecarboxylic acid;
2- 3-(1-Adamantyl)-4-methoxyphenylethynyl!-4-thiophenecarboxylic acid;
6- 3-(1-Adamantyl)-4-methoxyphenylethynyl!-2-naphthoic acid;
4- 3-(1-Adamantyl)-4-nonyloxyphenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-hexyloxyphenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-dodecyloxyphenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-cyclopropylmethoxyphenylethynyl!benzoic acid;
4- 2-Hexyloxy-5-(1-adamantyl)-4-hexyloxyphenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-heptyloxyphenylethynyl!benzoic acid;
6- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!nicotinic acid;
4- 2-Methoxy-5-(1-adamantyl)-4-methoxyphenylethynyl!benzoic acid;
4- 2-Methoxyethoxymethoxy-5-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoic acid;
4- 2-Methoxy-5-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-benzyloxyphenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzaldehyde;
4- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzenemethanol;
4- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzyl acetate;
4- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!phenyl acetate;
4- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!phenol;
4- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!phenoxyethylmorpholine;
4- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzamide;
N-Ethyl-4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzamide;
4- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoic acid morpholide;
2-Hydroxy-4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-(6-hydroxyhexyloxy)phenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-(6-methoxyhexyloxy)phenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4- 2-(4-morpholino)ethoxy!phenylethynyl!!benzoic acid;
4- 3-(1-Adamantyl)-4-(3-carbamoylpropyloxy)phenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-(5-carbamoylpentyloxy)phenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-(3-hydroxypropyloxy)phenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-(3-hydroxy-2-methylpropyloxy)phenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4- (2,2-dimethyl-1,3-dioxolan-4-methoxy)phenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-(2,3-dihydroxypropyloxy)phenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-methoxyethoxyethylphenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-methoxymethoxypropylphenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-methoxyethoxypropylphenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-acetoxybutoxyphenylethynyl!benzoic acid;
4- 3-(1-Adamantyl)-4-acetoxypropyloxyphenylethynyl!benzoic acid.
According to the present invention, the more particularly preferred compounds of formula (I) are those in which at least one, and preferably all, of the conditions given below are satisfied:
R1 is a --(CH2)p --CO--R8 radical;
R3 is an --O--CH2 --O--CH2 --CH2 --O--CH3 or .paren open-st.Y.paren close-st.n .paren open-st.CH2 .paren close-st.q R14 radical;
Ar is a radical selected from among those of formulae (a) and (e); and
R2 is a linear or branched alkyl radical having from 1 to 20 carbon atoms or, alternatively, an --O--R13 radical.
The present invention also features the processes for the preparation of the compounds of formula (I), in particular via the reaction schemes illustrated in FIGS. 1 and 2.
Thus, the compounds of formula I(a) can be prepared (FIG. 1) from the acetylene derivative (4) by conversion into a lithium and then zinc derivative (5). Such derivative is then coupled with the halogenated derivative (6) (preferably the iodinated or brominated derivative) in the presence of a palladium catalyst (preferably tetrakis(triphenylphosphine)palladium(0)) in a solvent such as THF.
The acetylene derivative (4) can, in its turn, be obtained from the brominated derivative (1) via three different techniques:
(i) either by conversion into an aldehyde compound (2) by reacting the magnesium or lithium derivative with dimethylformamide. The aldehyde (2) then reacts with carbon tetrabromide and triphenylphosphine to give a 2',2'-dibromostyrene derivative (3) which is then converted to the acetylene derivative (4) by means of a non-nucleophilic base such as n-butyllithium in an aprotic solvent such as tetrahydrofuran;
(ii) or by conversion to the acid derivative (7) by reacting the magnesium or lithium derivative with CO2. The acid (7), in the presence of a large excess of methyllithium, is then converted to a ketone derivative (8) which, by a sequence of reactions (treatment with a base such as lithium diisopropylamide and then with a dialkyl chlorophosphate and again with lithium diisopropylamide) is ultimately converted into the acetylene derivative (4);
(iii) or by conversion into the trimethylsilylacetylene derivative (9) by reaction with trimethylsilylacetylene in a solvent such as triethylamine in the presence of palladium acetate and triphenylphosphine and then desilylation in the presence either of potassium carbonate or of tetrabutylammonium fluoride.
In the aforesaid formulae and reactions R1, R2 and R3 are as defined above in respect of the compounds of formula (I) or are derivatives thereof which are suitably protected as to be compatible with the coupling conditions. In particular, when they represent the hydroxyl radical, the latter is preferably protected in the tert-butyldimethylsilyloxy or methoxyethoxymethoxy form. Deprotection is then carried out either in the presence of tetrabutylammonium fluoride or trimethylsilyl iodide or in acidic medium (for example HCl).
When R3 is a .paren open-st.CH2 .paren close-st.q CO--R8 radical or a --CH═CH--(CH2)t --R14 radical, the compounds are preferably prepared from the phenol derivative (9) according to the reaction scheme illustrated in FIG. 2, namely, conversion of the phenol derivative (9) into the triflate (10) and then nucleophilic substitution in the presence of a palladium catalyst (for example tetrakis(triphenylphosphine)palladium(0)) according to the general conditions described in S. Cacchi et al, Tetrahedron Letters, 27, 3931-4 (1986) or in W. J. Scott et al, J. Org. Chem., 50, 2302-8 (1985).
The present invention also features therapeutic/pharmaceutical applications of the compounds of formula (I).
Depending on the nature of the radicals used, these compounds exhibit either an agonist activity in the test for differentiation of embryonic teratocarcinoma cells (F9) in mice (Cancer Research, 43, p. 5268 (1983)) and/or in the test for inhibition of ornithine decarboxylase after induction by TPA in mice (Cancer Research, 38, p. 793-801 (1978)) or, in contrast, an antagonist activity with respect to the expression of one or more biological markers in the test for differentiation of embryonic teratocarcinoma cells (F9) in mice (Skin Pharmacol., 3, pp. 256-267 (1990)) and/or for the in vitro differentiation of human keratinocytes (Anal. Biochem., 192, pp. 232-236 (1991)).
The compounds according to the invention are particularly well suited in the following fields of therapy:
(1) for treating dermatological conditions associated with a keratinization disorder related to differentiation and proliferation, in particular for treating acne vulgaris, comedonic or polymorphic acne, acne rosacea, nodulocystic acne, acne conglobata, senile acne and secondary acnes such as solar, drug or occupational acne,
(2) for treating other types of keratinization disorders, in particular ichthyoses, ichthyosiform conditions, Darier's disease, palmoplantar keratoderma, leucoplakia and leucoplakiform conditions or cutaneous or mucosal (oral) lichen,
(3) for treating other dermatological conditions associated with a keratinization disorder manifesting an inflammatory and/or immunoallergic component and, in particular, all forms of psoriasis, whether cutaneous, mucosal or ungual, and even psoriatic rheumatism, or alternatively cutaneous or skin atopy, such as eczema, or respiratory atopy or alternatively gingival hypertrophy; the compounds can also be used in certain inflammatory conditions not exhibiting keratinization disorder,
(4) for treating all dermal or epidermal proliferations, whether benign or malignant, whether or not of viral origin, such as common warts, flat warts and epidermodysplasia verruciformis, florid oral papillomatoses and the proliferations which can be induced by ultraviolet radiation, in particular in the case of basal cell and prickle cell epithelioma,
(5) for treating other dermatological disorders, such as bullous dermatoses and collagen diseases,
(6) for treating certain opthalmological disorders, in particular corneopathies,
(7) for repairing or controlling aging of the skin, whether photoinduced or chronologic, or for reducing actinic keratoses and pigmentations, or any pathology associated with chronologic or actinic aging,
(8) for preventing or treating the stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy,
(9) for preventing or treating disorders of healing, or for preventing or for repairing stretch marks,
(10) for controlling disorders of the sebaceous function, such as hyperseborrhoea of acne or simple seborrhoea,
(11) for the treatment or prevention of cancerous or precancerous conditions,
(12) for the treatment of inflammatory conditions such as arthritis,
(13) for the treatment of any condition of viral origin at the cutaneous or general level,
(14) for the prevention or treatment of alopecia,
(15) for the treatment of dermatological or general conditions including an immunological component,
(16) for the treatment of ailments of the cardiovascular system, such as arteriosclerosis,
(17) for the treatment or prevention of osteoporosis.
For the aforesaid therapeutic or pharmaceutical applications, the compounds according to the invention can advantageously be used in combination with other compounds displaying a retinoid-type activity, with vitamins D or derivatives thereof, with corticosteroids, with compounds which control free radicals, α-hydroxy or α-keto acids or derivatives thereof, or alternatively with ion channel blockers. By "vitamins D or derivatives thereof" are intended, for example, derivatives of vitamin D2 or D3 and in particular 1,25-dihydroxyvitamin D3. By "compounds which control free radicals" are intended, for example, α-tocopherol, superoxide dismutase, ubiquinol or certain metal chelating agents. By "α-hydroxy or α-keto acids or derivatives thereof" are intended, for example, lactic, malic, citric, glycolic, mandelic, tartaric, glyceric or ascorbic acids or salts, amides or esters thereof. By "ion channel blockers" are intended, for example, minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) and derivatives thereof.
The present invention thus also features medicinal compositions containing at least one compound of formula (I), one of its chiral or geometric isomers, or one of its pharmaceutically accepetable salts, or other derivatives thereof.
The pharmaceutical/therapeutic compositions of the present invention, intended especially for treating the aforesaid disease states comprise a pharmaceutically acceptable vehicle, carrier or diluent which is compatible with the mode or regime of administration selected for the given composition, at least one compound of formula (I), one of its chiral or geometric isomers, or one of the salts, etc., thereof.
The administration of the compounds according to the invention can be carried out systemically, enterally, parenterally, topically or ocularly.
For enteral administration, the medicinal/pharmaceutical compositions may be in the form of tablets, hard gelatin capsules, dragees, syrups, suspensions, solutions, elixirs, powders, granules, emulsions or polymeric or lipid microspheres or nanospheres or vesicles which permit a controlled release. For parenteral administration, the compositions may be in the form of solutions or suspensions for perfusion or for injection.
The compounds according to the invention are generally administered at a daily dose of approximately 0.01 mg/kg to 100 mg/kg by body weight, and this at the rate or regime of 1 to 3 doses per diem.
For topical administration, the pharmaceutical compositions based on compounds according to the invention are more particularly intended for treating the skin and the mucosal membranes and can then be provided in the form of ointments, creams, milks, salves, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They can also be provided in the form of polymeric or lipid vesicles or nanospheres or microspheres or of polymeric patches and of hydrogels which permit controlled release. These compositions for topical administration can, moreover, be provided either in anhydrous form or in an aqueous form, according to the particular clinical indication.
For ocular administration, they are principally eye washes.
These compositions for a topical or ocular application contain at least one compound of formula (I), or one of its optical or geometric isomers or, alternatively one of its salts, etc., at a concentration preferably ranging from 0.001% to 5% by weight relative to the total weight of the composition.
The compounds of formula (I) according to the invention also find application in the cosmetics field, in particular for body and hair care/hygiene, and especially for the treatment of skins tending to develop acne, for hair regrowth and combating hair loss, for combating the greasy appearance of the skin or the hair, for protecting against the deleterious effects of sunlight or in the treatment of physiologically dry skin, and for preventing and/or for controlling photoinduced or chronologic aging.
For cosmetic applications, the compounds according to the invention can, moreover, be advantageously be used in combination with other compounds displaying a retinoid-type activity, with vitamins D or derivatives thereof, with corticosteroids, with compounds which control free radicals, with α-hydroxy or α-keto acids or derivatives thereof, or alternatively with ion channel blockers, all of these various active agents being as defined above.
The present invention therefore also features cosmetic compositions comprising a cosmetically acceptable vehicle, carrier or diluent which is suitable for topical application, at least one compound of formula (I) or one of its chiral or geometric isomers, or one of its salts, etc. Such cosmetic compositions are advantageously in the form of a cream, milk, lotion, ointment, gel, polymeric or lipid vesicles or nanospheres or microspheres, soap or shampoo.
The concentration of the compound of formula (I) in the cosmetic compositions according to the invention advantageously ranges from 0.001% and 3% by weight relative to the total weight of the composition.
The medicinal and cosmetic compositions according to the invention can, in addition, contain inert or even pharmacodynamically or cosmetically active additives or combinations of these additives, and, especially: wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients; hydrating or moisturizing agents such as glycerol, PEG 400, thiamorpholinone and its derivatives or alternatively urea; anti-seborrhoeic or anti-acne agents such as S-carboxymethylcysteine, S-benzylcysteamine, their salts or derivatives thereof, or benzoyl peroxide; antibiotics such as erythromycin and esters thereof, neomycin, clindamycin and esters thereof, or tetracyclines; anti-fungal agents such as ketoconazole or 4,5-polymethylene-3-isothiazolidones; agents promoting hair regrowth, such as Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) and derivatives thereof, Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) and phenytoin (5,5-diphenylimidazolidine-2,4-dione); non-steroidal anti-inflammatory agents; carotenoids and especially β-carotene; anti-psoriatic agents such as anthralin and its derivatives; and, lastly, eicosa-5,8,11,14-tetraynoic and eicosa-5,8,11-triynoic acids, and esters and amides thereof.
The compositions according to the invention can also contain flavor-enhancing agents, preservatives such as the esters of para-hydroxybenzoic acid, stabilizing agents, moisture-regulating agents, pH-regulating agents, osmotic-pressure-modifying agents, emulsifying agents, UV-A and UV-B screening agents and antioxidants such as α-tocopherol, butylated hydroxyanisole or butylated hydroxytoluene.
In order to further illustrate the present invention and the advantages thereof, the following specific examples are given, it being understood that same are intended only as illustrative and in nowise limitative.
EXAMPLE 1
Preparation of 4- 3-(1-adamantyl)-4-methoxyphenylethynyl!benzoic acid
(a) Synthesis of 3-(1-adamantyl)-4-methoxyphenylacetylene
4.7 ml (33 mmol) of diisopropylamine and 40 ml of THF were introduced into a three-necked flask under a stream of nitrogen. 20.6 ml (33 mmol) of n-butyllithium (1.6M in hexane) were added dropwise at -78° C. and stirring was carried out at this same temperature for 15 minutes. A solution of 8.5 g (30 mmol) of 3-(1-adamantyl)-4-methoxyacetophenone in 50 ml of THF was then added. After stirring for one hour at -78° C., the solution was treated with 4.8 ml (33 mmol) of diethyl chlorophosphate and the temperature was permitted to return to room temperature. This solution was transferred to a lithium diisopropylamide solution which had been prepared using 9.35 ml (66 mmol) of diisopropylamine and 41 ml (66 mmol) of n-butyllithium (1.6M in hexane) in 90 ml of THF at -78° C. The temperature was permitted to return to room temperature and the mixture was stirred for twelve hours.
The reaction mixture was poured into ice-cold water and the pH was adjusted to 1 with hydrochloric acid (5N). Extraction was carried out with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (10/90). After evaporation of the solvents, 4.3 g (54%) of the expected acetylene derivative were collected, which compound had the melting point 121°-2° C.
(b) Synthesis of methyl 4- 3-(1-adamantyl)-4-methoxyphenylethynyl!benzoate
4.4 ml (7 mmol) of n-butyllithium (1.6M in hexane) were added dropwise at 0° C. to a solution of 1.8 g (6.8 mmol) of 3-(1-adamantyl)-4-methoxyphenylacetylene in 20 ml of THF and the mixture was stirred for thirty minutes at room temperature. The mixture was cooled to 0° C. and 1.05 g (7.7 mmol) of anhydrous ZnCl2 was added and the mixture was stirred for one hour at room temperature.
1.3 g (1.1 mmol) of tetrakis(triphenylphosphine)palladium(0) and 13 ml of THF were introduced into a three-necked flask and a solution of 1.77 g (6.7 mmol) of methyl 4-iodobenzoate was added. Stirring was carried out at room temperature for thirty minutes and the zinc solution prepared above was added dropwise. The reaction mixture was stirred at room temperature for twelve hours, was then poured into a mixture of 80 ml of hydrochloric acid (3N) and ice-cold water and finally extracted with ethyl acetate.
The organic phase was separated by settling, washed with water, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of hexane and ethyl ether (90/10). After evaporation of the solvents, 970 mg (36%) of the expected methyl ester were collected, which ester had the melting point 197°-8° C.
(c) Synthesis of 4- 3-(1-adamantyl)-4-methoxyphenylethynyl!benzoic acid
966 mg (2.4 mmol) of the ester prepared in part (b) above and 20 ml of methanolic sodium hydroxide (2N) were introduced into a round-bottomed flask and heating was carried out at reflux for one hour. The reaction mixture was evaporated to dryness, the residue was taken up in water, acidification was carried out with concentrated hydrochloric acid and the solids which had precipitated were filtered.
After recrystallization from ethyl alcohol, 660 mg (71%) of the expected acid were collected, which acid had the melting point 307°-10° C.
EXAMPLE 2
Preparation of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxy-phenylethynyl!benzoic acid
(a) Synthesis of 3-(1-adamantyl)-1-bromo-4-methoxyethoxymethoxybenzene
3.8 g (0.13 mol) of sodium hydride (80% in oil) and 50 ml of DMF were introduced into a three-necked flask under a stream of nitrogen, a solution of 40 g (0.13 mol) of 2-(1-adamantyl)-4-bromophenol in 100 ml of DMF was then added dropwise and stirring was carried out until gas evolution has ceased. A solution of 18 ml (0.15 mol) of 2-methoxyethoxymethyl chloride in 20 ml of DMF was then added dropwise and stirring was carried out for four hours at room temperature. The reaction mixture was then poured into water and extracted with ethyl ether and the organic phase was separated by settling, washed with water, dried over magnesium sulphate and evaporated.
The residue was purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (50/50). After evaporation of the solvents, 40.1 g (78%) of the expected product are collected, which compound had the melting point 69°-70° C.
(b) Synthesis of 3-(1-adamantyl)-4-methoxyethoxymethoxybenzoic acid
The compound obtained in part (a) above (28.5 g, 72 mmol) was dissolved in 200 ml of THF. The solution obtained was added dropwise over magnesium (2.4 g, 100 mmol) and iodine crystals. After introduction, heating was carried out at reflux for two hours, cooling was carried out to -78° C. and a stream of CO2 was charged therein for one hour.
The temperature was permitted to increase to room temperature, the reaction mixture is poured into a saturated aqueous ammonium chloride solution and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
The residue obtained was triturated in hexane, filtered and dried. 15.5 g (60%) of the expected acid were collected, which acid had the melting point 115°-6° C.
(c) Synthesis of 3-(1-adamantyl)-4-methoxyethoxymethoxyacetoxyphenone
15.5 g (43 mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxybenzoic acid and 300 ml of anhydrous ethyl ether were introduced into a three-necked flask under a stream of nitrogen. 80 ml (0.13 mol) of methyllithium (1.6M in ether) were added dropwise at -20° C. and stirring was then carried out for three hours at room temperature. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
15.4 g (100%) of the expected acetophenone were collected in the form of a slightly yellow oil.
(d) Synthesis of 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylacetylene
In a manner analogous to Example 1(a) above, from 11.8 g (33 mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxyacetophenone, 6.3 g (57%) of the expected acetylene were obtained, which acetylene compound had the melting point 81°-2° C.
(e) Synthesis of methyl 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoate
In a manner analogous to Example 1(a) above, by reaction of 1.5 g (4.4 mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylacetylene with 1.2 g (4.4 mmol) of methyl 4-iodobenzoate and after purification by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (70/30), 1.5 g (72%) of the expected methyl ester were obtained, which ester had the melting point 92°-3° C.
(f) Synthesis of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoic acid
In a manner analogous to Example 1(c) above, from 730 mg (1.5 mmol) of the ester prepared in part (e) above, 600 mg (87%) of the expected acid were obtained, which acid had the melting point 203°-4° C.
EXAMPLE 3
Preparation of 4- 3-(1-adamantyl)-4-hydroxyphenylethynyl!benzoic acid
(a) Synthesis of methyl 4- 3-(1-adamantyl)-4-hydroxphenylethynyl!benzoate
1.3 g (2.7 mmol) of methyl 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoate and 50 ml of anhydrous dichloromethane were introduced into a round-bottomed flask and 2.7 ml (2.7 mmol) of boron trichloride (1M in CH2 Cl2) were added dropwise at 0° C.
The reaction mixture was stirred at room temperature for one hour, was poured into water and was extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
The residue obtained was triturated in a mixture of hexane and ethyl ether, filtered and dried. 910 mg (91%) of the expected compound were collected, which compound had the melting point 232°-3° C.
(b) Synthesis of 4- 3-(1-adamantyl)-4-hydroxyphenylethynyl!benzoic acid
In a manner analogous to Example 1(c) above, from 850 mg (2.2 mmol) of methyl 4- 3-(1-adamantyl)-4-hydroxyphenylethynyl!benzoate, 720 mg (88%) of the expected acid were collected, which acid had the melting point 254°-5° C.
EXAMPLE 4
Preparation of 5- 3-(1-adamantyl)-4-hydroxyphenylethynyl!-2-thiophenecarboxylic acid
(a) Synthesis of methyl 5- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!-2-thiophenecarboxylate
In a manner analogous to Example 1(b) above, by reaction of 1.5 g (4.4 mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylacetylene with 1 g (4.4 mmol) of methyl 5-bromo-2-thiophene, carboxylate, 1.4 g (67%) of the expected methyl ester were obtained in the form of an oil.
(b) Synthesis of methyl 5- 3-(1-adamantyl)-4-hydroxyphenylethynyl!-2-thiophenecarboxylate
In a manner analogous to Example 3(a) above, from 1.2 g (2.5 mmol) of the ester obtained in part (A) above, 847 mg (86%) of methyl 5- 3-(1-adamantyl)-4-hydroxyphenylethynyl!-2-thiophenecarboxylate were obtained, which compound had the melting point 207°-8° C.
(c) Synthesis of 5- 3-(1-adamantyl)-4-hydroxyphenylethynyl!-2-thiophenecarboxylic acid
In a manner analogous to Example 1(c) above, from 360 mg (0.9 mmol) of the methyl ester obtained in part (b) above, 300 mg (86%) of 5- 3-(1-adamantyl)-4-hydroxyphenylethynyl!-2-thiophenecarboxylic acid were obtained, which acid had the melting point 249°-50° C.
EXAMPLE 5
Preparation of 5- 3-(1-adamantyl)-4-methoxyphenylethynyl!-2-thiophenecarboxylic acid
(a) Synthesis of methyl 5- 3-(1-adamantyl)-4-methoxyphenylethynyl!-2-thiophenecarboxylate
36 mg (1.2 mmol) of sodium hydride (80% in oil) and 20 ml of DMF were introduced into a three-necked flask under a stream of nitrogen and a solution of 392 mg (1 mmol) of methyl 5- 3-(1-adamantyl)-4-hydroxyphenylethynyl!-2-thiophenecarboxylate in 10 ml of DMF were added dropwise.
The reaction mixture was stirred for thirty minutes, 75 μl (1.2 mmol) of iodomethane were then added and the reaction mixture was stirred at room temperature for four hours. The reaction mixture was then poured into water and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
The residue was triturated in hexane, filtered and dried. 385 mg (95%) of the expected compound were collected, which compound had the melting point 137°-8° C.
(b) Synthesis of 5- 3-(1-adamantyl)-4-methoxyphenylethynyl!-2-thiophenecarboxylic acid
In a manner analogous to Example 1(c) above, from 370 mg (0.9 mmol) of the methyl ester obtained in part (a) above, 320 mg (90%) of 5- 3-(1-adamantyl)-4-methoxyphenylethynyl!-2-thiophenecarboxylic acid were obtained, which acid had the melting point 244°-5° C.
EXAMPLE 6
Preparation of 2- 3-(1-adamantyl)-4-methoxyphenylethynyl!-4-thiophenecarboxylic acid
(a) Synthesis of ethyl 2- 3-(1-Adamantyl)-4-methoxyphenylethynyl!-4-thiophenecarboxylate
In a manner analogous to Example 1(b) above, by reaction of 3.2 g (12 mmol) of 3-(1-adamantyl)-4-methoxyphenylacetylene with 2.8 g (12 mmol) of ethyl 2-bromo-4-thiophenecarboxylate, there were obtained, after chromatography on a silica column eluted with a mixture of hexane and ethyl acetate, 2.4 g (48%) of the expected ethyl ester with the melting point 88°-90° C.
(b) Synthesis of 2- 3-(1-adamantyl)-4-methoxyphenylethynyl!-4-thiophenecarboxylic acid
In a manner analogous to Example 1(c) above, from 2.3 g (5.4 mmol) of the ester obtained in part (a) above, there was obtained, after recrystallization from ethyl alcohol, 1.8 g (86%) of 2- 3-(1-adamantyl)-4-methoxyphenylethynyl!-4-thiophenecarboxylic acid with the melting point 244°-6° C.
EXAMPLE 7
Preparation of 6- 3-(1-adamantyl)-4-methoxyphenylethynyl!-2-naphthoic acid
(a) Synthesis of methyl 6- 3-(1-adamantyl)-4-methoxyphenylethynyl!-2-naphthoate
In a manner analogous to Example 1(b) above, from 4.5 g (16.9 mmol) of 3-(1-adamantyl)-4-methoxyphenylacetylene and 4.45 g (16.8 mmol) of methyl 6-bromo-2-naphthoate, 3.8 g (50%) of the expected methyl ester were obtained, which ester had the melting point 233°-4° C.
(b) Synthesis of 6- 3-(1-adamantyl)-4-methoxyphenylethynyl!-2-naphthoic acid
In a manner analogous to Example 1(c) above, from 3.8 g (8.4 mol) of the ester obtained in part (a) above, 2.2 g (62%) of 6- 3-(1-adamantyl)-4-methoxyphenylethynyl!-2-naphthoic acid were obtained, which acid had the melting point 307°-9° C.
EXAMPLE 8
Preparation of 4- 3-(1-adamantyl)-4-nonyloxyphenylethnyl!benzoic acid
(a) Synthesis of methyl 4- 3-(1-adamantyl)-4-nonyloxyphenylethynyl!benzoate
75 mg (2.6 mmol) of sodium hydride (80% in oil) and 10 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. A solution of 1 g (2.6 mmol) of methyl 4- 3-(1-adamantyl)-4-hydroxyphenylethynyl!benzoate dissolved in 70 ml of DMF was added dropwise and stirring was carried out at room temperature until gas evolution had ceased. 610 μl (3.1 mmol) of 1-iodononane were then added dropwise and stirring was carried out at room temperature for four hours. The reaction mixture was poured into ice-cold water and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulphate and evaporated.
The residue obtained as purified by chromatography on a silica column eluted with a mixture of dichloromethane and heptane (50/50). After evaporation of the solvents, 960 mg (72%) of the expected methyl ester were collected, which ester had the melting point 112°-5° C.
(b) Synthesis of 4- 3-(1-adamantyl)-4-nonyloxyphenylethynyl!benzoic acid
960 mg (1.9 mmol) of the immediately preceding methyl ester and 25 ml of a 2N methanolic sodium hydroxide solution were introduced into a round-bottomed flask and heating was carried out at reflux for two hours. The reaction mixture was evaporated to dryness, the residue was taken up in water acidifed to pH 1 with hydrochloric acid and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
The residue obtained was triturated in a mixture of dichloromethane and heptane (20/80), filtered and dried. 630 mg (67%) of 4- 3-(1-adamantyl)-4-nonyloxyphenylethynyl!benzoic acid were collected, which acid had the melting point 224°-6° C.
EXAMPLE 9
Preparation of 4- 3-(1-adamantyl)-4-hexyloxyphenylethynyl!benzoic acid
(a) Synthesis of methyl 4- 3-(1-adamantyl)-4-hexyloxyphenylethynyl!benzoate
In a manner analogous to Example 8(a), by reaction of 1 g (2.6 mmol) of methyl 4- 3-(1-adamantyl)-4-hydroxyphenylethynyl!benzoate with 460 μl (3.1 mmol) of 1-iodohexane, 900 mg of the expected methyl ester were obtained, which ester had the melting point 140°-3° C.
(b) Synthesis of 4- 3-(1-adamantyl)-4-hexyloxyphenylethynyl!benzoic acid
In a manner analogous to Example 8(b), from 900 mg (1.9 mmol) of the preceding methyl ester, 700 mg (80%) of 4- 3-(1-adamantyl)-4-hexyloxyphenylethynyl!-benzoic acid were obtained, which acid had the melting point 260°-2° C.
EXAMPLE 10
Preparation of 4- 3-(1-adamantyl)-4-dodecyloxyphenylethynyl!benzoic acid
(a) Synthesis of methyl 4- 3-(1-adamantyl)-4-dodecyloxyphenylethynyl!benzoate
In a manner analogous to Example 8(a), by reaction of 1 g (2.6 mmol) of methyl 4- 3-(1-adamantyl)-4-hydroxyphenylethynyl!benzoate with 750 μl (3.1 mmol) of 1-bromododecane, 1.1 g (77%) of the expected methyl ester was obtained, which ester had the melting point 101°-4° C.
(b) Synthesis of 4- 3-(1-adamantyl)-4-dodecyloxyphenylethynyl!benzoic acid
In a manner analogous to Example 8(b), from 1.1 g (2 mmol) of the preceding methyl ester, 1 g (93%) of 4- 3-(1-adamantyl)-4-dodecyloxyphenylethynyl!benzoic acid was obtained, which acid had the melting point 225°-7° C.
EXAMPLE 11
Preparation of 4- 3-(1-adamantyl)-4-cyclopropylmethoxyphenylethynyl!benzoic acid
(a) Synthesis of methyl 4- 3-(1-Adamantyl)-4-cyclopropylmethoxyphenylethynyl!benzoate
In a manner analogous to Example 8(a), by reaction of 1 g (2.6 mmol) of methyl 4- 3-(1-adamantyl)-4-hydroxyphenylethynyl!benzoate with 300 μl (3.1 mmol) of bromomethylcyclopropane, 700 mg (61%) of the expected methyl ester were obtained, which ester had the melting point 185°-6° C.
(b) Synthesis of 4- 3-(1-adamantyl)-4-cyclopropylmethoxyphenylethynyl!benzoic acid
In a manner analogous to Example 8(b), from 700 mg (1.6 mmol) of the preceding methyl ester, 570 mg (84%) of 4- 3-(1-adamantyl)-4-cyclopropylmethoxyphenylethynyl!benzoic acid were obtained, which acid had the melting point 302°-5° C.
EXAMPLE 12
Preparation of 4- 2-hexyloxy-5-(1-adamantyl)-4-hexyloxyphenylethynyl!benzoic acid
(a) Synthesis of 2,4-dihydroxy-5-(1-adamantyl)benzaldehyde
5 g (36.2 mmol) of 2,4-dihydroxybenzaldehyde, 5.8 g (38.1 mmol) of 1-adamantanol of 200 ml of dichloromethane were introduced into a round-bottomed flask. 2 ml of concentrated sulfuric acid were added and the mixture was stirred at room temperature for eight hours. The reaction mixture was evaporated to dryness, the residue was taken up in water, neutralized with sodium bicarbonate and extracted with ethyl ether and the extract was dried over magnesium sulfate and evaporated.
The residue obtained was triturated with a mixture of dichloromethane and heptane (40/60) and the solid was filtered and dried. 6.8 g (69%) of the expected compound were collected, which compound had the melting point 165°-8° C.
(b) Synthesis of 2,4-dihexyloxy-5-(1-adamantyl)benzaldehyde
1.3 g (35.2 mmol) of sodium hydride (80% in oil) and 50 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. A solution of 4.8 g (17.6 mmol) of 2,4-dihydroxy-5-(1-adamantyl)-benzaldehyde dissolved in 70 ml of DMF was added dropwise and stirring was carried out at room temperature until gas evolution has ceased. 6.5 ml (35.2 mmol) of 1-iodohexane were then added dropwise and stirring was carried out at room temperature for four hours.
The reaction mixture was poured into ice-cold water and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
The residue obtained was purified by chromatography on a silica column eluted with dichloromethane. After evaporation of the solvents, 5.5 g (71%) of the expected compound were collected in the form of a slightly blue oil.
(c) Synthesis of 2',2'-dibromo-2,4-dihexyloxy-5-(1-adamantyl)styrene
5.5 g (12.5 mmol) of 2,4-dihexyloxy-5-(1-adamantyl)benzaldehyde and 100 ml of dichloromethane were introduced into a round-bottomed flask. 8.3 g (25 mmol) of carbon tetrabromide, 6.5 g (25 mmol) of triphenylphosphine and 1.6 g (25 mmol) of zinc powder were added successively and stirring was carried out at room temperature for two hours. The reaction mixture was evaporated and the residue obtained purified by chromatography on a silica column eluted with dichloromethane. 3 g (40%) of the expected compound were collected in the form of a yellow oil.
(d) Synthesis of 2,4-dihexyloxy-5-(1-adamantyl)phenylacetylene
3 g (5 mmol) of 2',2'-dibromo-2,4-dihexyloxy-5-(1-adamantyl)styrene and 50 ml of THF were introduced into a three-necked flask under a stream of nitrogen. 4 ml (10 mmol) of an n-butyllithium solution (2.5M in hexane) were added dropwise at -78° C. and the temperature was permitted to increase to room temperature for one hour. The reaction mixture was poured into water and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
The residue obtained was purified by chromatography on a silica column eluted with dichloromethane. 1.9 g (86%) of the expected acetylene derivative were collected in the form of a brown oil.
(e) Synthesis of methyl 4- 2-hexyloxy-5-(1-adamantyl)-4-hexyloxyphenylethynyl!benzoate
1.8 g (4.1 mmol) of 2,4-dihexyloxy-5-(1-adamantyl)phenylacetylene, 1.2 g (4.5 mmol) of methyl 4-iodobenzoate and 15 ml of triethylamine were introduced into a three-necked flask. The reaction mixture was degassed with nitrogen for 15 min, 100 mg of copper iodide and 260 mg (0.37 mmol) of bis(triphenylphosphine)-palladium(II) chloride were added and stirring was carried out at room temperature for twelve hours. The reaction mixture was evaporated to dryness, the residue was taken up in water and ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and heptane (20/80). After evaporation of the solvents, 1.7 g (72%) of the expected methyl ester were collected.
(f) Synthesis of 4- 2-hexyloxy-5-(1-adamantyl)-4-hexyloxyphenylethynyl!benzoic acid
In a manner analogous to Example 8(b), from 1.7 g (3 mmol) of the preceding methyl ester, 1.5 g (90%) of the expected acid was obtained, which acid had the melting point 213°-4° C.
EXAMPLE 13
Preparation of 4- 3-(1-adamantyl)-4-heptyloxyphenylethynyl!benzoic acid
(a) Synthesis of methyl 4- 3-(1-adamantyl)-4-heptyloxyphenylethynyl!benzoate
In a manner analogous to Example 8(a), by reaction of 500 mg (1.3 mmol) of methyl 4- 3-(1-adamantyl)-4-hydroxyphenylethynyl!benzoate with 250 μl (1.56 mmol) of 1-bromoheptane, 500 mg (82%) of the expected methyl ester were obtained.
(b) Synthesis of 4- 3-(1-adamantyl)-4-heptyloxyphenylethynyl!benzoic acid
In a manner analogous to Example 8(b), from 500 mg (1.07 mmol) of the preceding methyl ester, 350 mg (70%) of 4- 3-(1-adamantyl)-4-heptyloxyphenylethynyl!benzoic acid were obtained, which acid had the melting point 256°-7° C.
EXAMPLE 14
Preparation of 6- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!nicotinic acid
(a) Synthesis of methyl 6- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!nicotinate
In a manner analogous to Example 12(e), by reaction of 2.5 g (7.4 mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylacetylene with 1.93 g (7.4 mmol) of methyl 6-iodonicotinate, 1.98 g (56%) of the expected methyl ester was obtained, which ester had the melting point 86°-7° C.
(b) Synthesis of 6- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!nicotinic acid
In a manner analogous to Example 8(b), from 1.5 g (3.1 mmol) of the preceding methyl ester, 1.4 g (95%) of the expected acid was obtained, which acid had the melting point 204°-5° C.
EXAMPLE 15
Preparation of 4- 2-methoxy-5-(1-adamantyl)-4-methoxyphenylethynyl!benzoic acid
(a) Synthesis of 2,4-dimethoxy-5-(1-adamantyl)benzaldehyde
In a manner analogous to Example 12(b), by reaction of 1.1 g (3.8 mmol) of 2,4-dihydroxy-5-(1-adamantyl)benzaldehyde with 620 μl (9.8 mmol) of methyl iodide, 1 g (87%) of the expected compound was obtained, which compound had the melting point 152°-4° C.
(b) Synthesis of 2'2'-dibromo-2.4-dimethoxy-5-(1-adamantyl)styrene
In a manner analogous to Example 12(c), from 1.8 g (6 mmol) of the preceding aldehyde, 1.2 g (44%) of 2'2'-dibromo-2,4-dimethoxy-5-(1-adamantyl)styrene was obtained, which compound had the melting point 176°-8° C.
(c) Synthesis of 2,4-dimethoxy-5-(1-adamantyl)phenylacetylene
In a manner analogous to Example 12(d), from 1.2 g (2.6 mmol) of the preceding product, 300 mg (38%) of the expected acetylene derivative were obtained, which derivative had the melting point 210°-3° C.
(d) Synthesis of methyl 4- 2-methoxy-5-(1-adamantyl)-4-methoxyphenylethynyl!benzoate
In a manner analogous to Example 12(e) by reaction of 300 mg (1 mmol) of 2,4-dimethoxy-5-(1-adamantyl)phenylacetylene with 265 mg (1 mmol) of methyl-4-iodobenzoate, 350 mg (80%) of the expected methyl ester were obtained, which ester had the melting point 186°-8° C.
(e) Synthesis of 4- 2-methoxy-5-(1-adamantyl)-4-methoxyphenylethynyl!benzoic acid
In a manner analogous to Example 8(b), from 350 mg (0.8 mmol) of the preceding methyl ester, 290 mg (85%) of 4- 2-methoxy-5-(1-adamantyl)-4-methoxyphenylethynyl!benzoic acid were obtained, which acid had the melting point 274°-8° C.
EXAMPLE 16
Preparation of 4- 2-methoxyethoxymethoxy-5-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoic acid
(a) Synthesis of 2,4-dimethoxyethoxymethoxy-5-(1-adamantyl)benzaldehyde
In a manner analogous to Example 12(b), by reaction of 25 g (92 mmol) of 2,4-dihydroxy-5-(1-adamantyl)benzaldehyde with 26.2 ml (230 mmol) of methoxyethoxymethyl chloride, 31 g (75%) of the expected compound were obtained in the form of a yellow oil.
(b) Synthesis of 2',2'-dibromo-2,4-dimethoxyethoxymethoxy-5-(1-adamantyl)styrene
In a manner analogous to Example 12(c), from 4.5 g (10 mmol) of the preceding aldehyde, 5.5 g (90%) of 2',2'-dibromo-2,4-dimethoxyethoxymethoxy-5-(1-adamantyl)styrene were obtained in the form of a brown oil.
(c) Synthesis of 2,4-dimethoxyethoxymethoxy-5-(1-adamantyl)phenylacetylene
In a manner analogous to Example 12(d), from 5.5 g (9.1 mmol) of the preceding product, 900 mg (23%) of the expected acetylene derivative were obtained in the form of a colorless oil.
(d) Synthesis of methyl 4- 2-methoxyethoxymethoxy-5-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoate
In a manner analogous to Example 12(e), by reaction of 900 mg (2 mmol) of 2,4-dimethoxyethoxymethoxy-5-(1-adamantyl)phenylacetylene with 530 mg (2 mmol) of methyl 4-iodobenzoate, 950 mg (81%) of the expected methyl ester were obtained in the form of a brown oil.
(e) Synthesis of 4- 2-methoxyethoxymethoxy-5-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoic acid
In a manner analogous to Example 8(b), from 950 mg (1.6 mmol) of the preceding methyl ester, 730 mg (79%) of 4- 2-methoxyethoxymethoxy-5-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoic acid were obtained, which acid had the melting point 131°-5° C.
EXAMPLE 17
Preparation of 4- 2-methoxy-5-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoic acid
(a) Synthesis of 2-hydroxy-4-methoxyethoxymethoxy-5-(1-adamantyl)benzaldehyde
5 g (11.2 mmol) of 2,4-dimethoxyethoxymethoxy-5-(1-adamantyl)benzaldehyde and 100 ml of dichloromethane were introduced into a three-necked flask under a stream of nitrogen. 11.2 ml of a boron trichloride solution (1M in hexane) were added dropwise at -78° C. and stirring was carried out at the same temperature for 18 hours. The reaction mixture was poured into ice-cold water and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
The residue obtained was purified by chromatography on a silica column eluted with dichloromethane. After evaporation of the solvents, 3.1 g (77%) of 2-hydroxy-4-methoxyethoxymethoxy-5-(1-adamantyl)benzaldehyde were collected, which compound had the melting point 102°-4° C.
(b) Synthesis of 2-methoxy-4-methoxyethoxymethoxy-5-(1-adamantyl)benzaldehyde
In a manner analogous to Example 12(b), by reaction of 2.9 g (8 mmol) of the preceding aldehyde derivative with 550 μl (8.8 mmol) of methyl iodide, 2.1 g (70%) of the expected compound were obtained, which compound had the melting point 48°-50° C.
(c) Synthesis of 2',2'-dibromo-2-methoxy-4-methoxyethoxymethoxy-5-(1-adamantyl)styrene
In a manner analogous to Example 12(c), from 2.1 g (5.6 mmol) of the preceding aldehyde, 2 g (67%) of 2',2'-dibromo-2-methoxy-4-methoxyethoxymethoxy-5-(1-adamantyl)styrene were obtained in the form of a colorless oil.
(d) Synthesis of 2-methoxy-4-methoxyethoxymethoxy-5-(1-adamantyl)phenylacetylene
In a manner analogous to Example 12(d), from 2 g (3.8 mmol) of the preceding product, 1.3 g (93%) of the expected acetylene derivative were obtained in the form of a colorless oil.
(e) Synthesis of methyl 4- 2-methoxy-5-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoate
In a manner analogous to Example 12(e), by reaction of 1.3 g (3.5 mmol) of 2-methoxy-4-methoxyethoxymethoxy-5-(1-adamantyl)phenylacetylene with 920 mg (3.5 mmol) of methyl 4-iodobenzoate, 1.3 g (73%) of the expected methyl ester was obtained, which ester had the melting point 152°-5° C.
(f) Synthesis of 4- 2-methoxy-5-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl benzoic acid
In a manner analogous to Example 8(b), from 1.3 g (2.6 mmol) of the preceding methyl ester, 1.05 g (83%) of 4- 2-methoxy-5-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoic acid was obtained, which acid had the melting point 210°-1° C.
EXAMPLE 18
Preparation of 4- 3-(1-adamantyl)-4-benzyloxyphenylethynyl!benzoic acid
(a) Synthesis of methyl 4- 3-(1-adamantyl)-4-benzyloxyphenylethynyl!benzoate
In a manner analogous to Example 8(a), by reaction of 1.1 g (2.8 mmol) of methyl 4- 3-(1-adamantyl)-4-hydroxyphenylethynyl!benzoate with 410 μl (3.4 mmol) of benzyl bromide, 800 mg (57%) of the expected methyl ester were obtained, which ester had the melting point 168°-9° C.
(b) Synthesis of 4- 3-(1-adamantyl)-4-benzyloxyphenylethynyl!benzoic acid
In a manner analogous to Example 8(b), from 800 mg (1.68 mmol) of the preceding methyl ester, 690 mg (88%) of 4- 3-(1-adamantyl)-4-benzyloxyphenylethynyl!benzoic acid were obtained, which acid had the melting point 288°-9° C.
EXAMPLE 19
Preparation of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzaldehyde
3 g (8.8 mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylacetylene, 1.8 g (9.7 mmol) of 4-bromobenzaldehyde and 50 ml of triethylamine were introduced into a three-necked flask. The reaction mixture was degassed with nitrogen for 15 min, 160 mg (1.7 mmol) of palladium(II) acetate and 350 mg (1.3 mmol) of triphenylphosphine were added and stirring was carried out at room temperature for twelve hours. The reaction mixture was evaporated to dryness, the residue was taken up in water and ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
The residue obtained was purified by chromatography on a silica column eluted with a mixture of ethyl acetate and heptane (10/90). After evaporation of the solvents, 1.39 g (34%) of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzaldehyde was collected, which compound had the melting point 120°-1° C.
EXAMPLE 20
Preparation of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzenemethanol
740 mg (1.6 mmol) of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzaldehyde were introduced into 40 ml of a mixture of THF and methanol (50/50) in a round-bottomed flask. 32 mg (0.8 mmol) of sodium borohydride were introduced in small amounts at 5° C. and the temperature was permitted to increase to room temperature. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
The residue obtained was purified by chromatography on a silica column eluted with a mixture of ethyl acetate and heptane (20/80). After evaporation of the solvents, 440 mg (60%) of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzenemethanol were collected, which compound had the melting point 103°-4° C.
EXAMPLE 21
Preparation of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxy-phenylethynyl!benzyl acetate
300 mg (0.7 mmol) of the alcohol obtained in the preceding example, 30 ml of dichloromethane and 230 μl (1.6 mmol) of triethylamine were introduced into a three-necked flask under a stream of nitrogen. 60 μl (0.8 mmol) of acetyl chloride were added and stirring was carried out at room temperature for two hours. The reaction mixture was poured into water and extracted with dichloromethane and the organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was crystallized from heptane and, after filtration, 190 mg (64%) of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzyl acetate were collected, which acetate had the melting point 83°-4° C.
EXAMPLE 22
Preparation of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxy-phenylethynyl!phenyl acetate
In a manner analogous to Example 12(e), by reaction of 2 g (5.9 mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylacetylene with 1.6 g (5.9 mmol) of 4-bromophenyl acetate, 1.2 g (43%) of the expected acetate were obtained, which acetate had the melting point 92°-3° C.
EXAMPLE 23
Preparation of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxy-phenylethynyl!phenol
In a manner analogous to Example 8(b), from 840 mg (1.8 mmol) of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!phenyl acetate, 710 mg (92%) of the expected phenol derivative were obtained, which derivative has the melting point 122°-3° C.
EXAMPLE 24
Preparation of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!phenoxyethylmorpholine
380 mg (0.9 mmol) of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!phenol, 200 mg of 4-(2-chloroethyl)morpholine hydrochloride, 300 mg (2 mmol) of potassium carbonate, 3 mg of potassium iodide and 50 ml of 2-butanone were introduced into a round-bottomed flask. The reaction mixture was heated at reflux for eight hours and was evaporated to dryness, the residue was taken up in water and ethyl acetate and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
The residue obtained was triturated in heptane and filtered. 330 mg (69%) of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!phenoxyethylmorpholine were collected, which compound had the melting point 168°-9° C.
EXAMPLE 25
Preparation of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxy-phenylethynyl!benzamide
(a) Synthesis of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoyl chloride
A solution of 3.14 g (6.8 mmol) of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoic acid in 100 ml of anhydrous dichloromethane was introduced into a round-bottomed flask, 1.4 ml (6.8 mmol) of dicyclohexylamine was added and stirring was carried out for one hour. 500 μl (6.8 mmol) of thionyl chloride were then added and stirring was carried out for one hour. Evaporation was carried out to dryness, the residue was taken up in anhydrous ethyl ether, the dicyclohexylamine salt was filtered and the filtrate was evaporated. 3.3 g (100%) of the crude acid chloride were collected, which chloride was used as is in the continuation of the synthesis to follow.
(b) Synthesis of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzamide
500 μl (9.1 mmol) of an aqueous ammonia solution (32%) and 20 ml of THF were introduced into a round-bottomed flask. A solution of 1.1 g (2.3 mmol) of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoyl chloride dissolved in 30 ml of THF was added dropwise and stirring was carried out at room temperature for three hours. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and methanol (98/2). After evaporation of the solvents, 550 mg (53%) of the expected amide were collected, which amide had the melting point 206°-7° C.
EXAMPLE 26
Preparation of N-ethyl-4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzamide
In a manner analogous to Example 25(b), by reaction of 1.1 g (2.3 mmol) of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoyl chloride with 600 μl (9.1 mmol) of ethylamine (70%), 520 mg (47%) of the expected ethylamide were obtained, which compound had the melting point 141°-2° C.
EXAMPLE 27
Preparation of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxy-phenylethynyl!benzoic acid morpholide
In a manner analogous to Example 25(b), by reaction of 1.1 g (2.3 mmol) of 4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoyl chloride with 600 μl (6.8 mmol) of morpholine, 930 mg (44%) of the expected amide were obtained, which amide had the melting point 142°-3° C.
EXAMPLE 28
Preparation of 2-hydroxy-4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoic acid
(a) Synthesis of methyl 2-hydroxy-4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoate
In a manner analogous to Example 12(e), by reaction of 690 mg (1.9 mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylacetylene with 530 mg (1.9 mmol) of methyl 2-hydroxy-4-iodobenzoate, 490 mg (52%) of the expected methyl ester were obtained, which ester had the melting point 96°-7° C.
(b) Synthesis of 2-hydroxy-4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoic acid
In a manner analogous to Example 8(b), from 500 mg (1 mmol) of methyl 2-hydroxy-4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoate, 360 mg (74%) of 2-hydroxy-4-(3- 1-adamantyl)-4-methoxyethoxymethoxy-phenylethynyl!benzoic acid were obtained, which acid had the melting point 186°-7° C.
EXAMPLE 29
Preparation of 4- 3-(1-adamantyl)-4-(6-hydroxyhexyloxy)phenylethynyl!benzoic acid
(a) Synthesis of methyl 4- 3-(1-adamantyl)-4-(6-hydroxyhexyloxy)phenylethynyl!benzoate
2 g (5.1 mmol) of methyl 4- 3-(1-adamantyl)-4-hydroxyphenylethynyl!benzoate, 1.1 ml (8.3 mmol) of 6-bromo-1-hexanol, 1.2 g (8.8 mmol) of potassium carbonate, 20 mg of potassium iodide and 100 ml of 2-butanone were introduced into a round-bottomed flask. The reaction mixture was heated at reflux for twelve hours and was evaporated to dryness, the residue was taken up in water and ethyl acetate and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
The residue obtained was purified by chromatography on a silica column eluted with a mixture of ethyl acetate and heptane (50/50). After evaporation of the solvents, 1.2 g (47%) of the expected compound was collected, which compound had a melting point 141°-2° C.
(b) Synthetis of 4- 3-(1-adamantyl)-4-(6-hydroxyhexyloxy)phenylethynyl!benzoic acid
In a manner analogous to Example 8(b), from 400 mg (0.8 mmol) of the preceding methyl ester, 330 mg (85%) of 4- 3-(1-adamantyl)-4-(6-hydroxyhexyloxy)phenylethynyl!benzoic acid were collected, which acid had the melting point 228°-9° C.
EXAMPLE 30
Preparation of 4- 3-(1-adamantyl)-4-(6-methoxyhexyloxy)phenylethynyl!benzoic acid
(a) Synthesis of methyl 4- 3-(1-adamantyl)-4-(6-methoxyhexyloxy)phenylethynyl!benzoate
390 mg (0.8 mmol) of methyl 4- 3-(1-adamantyl)-4-(6-hydroxyhexyloxy)phenylethynyl!benzoate, 10 ml of toluene and 200 μl of a 50% sodium hydroxide solution were introduced into a round-bottomed flask. 20 mg (5.4 mmol) of tetrabutylammonium iodide and 100 μl (0.9 mmol) of dimethyl sulfate were added and stirring was carried out at room temperature for four hours. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulphate and evaporated.
The residue obtained was purified by chromatography on a silica column eluted with a mixture of ethyl acetate and heptane (10/90). After evaporation of the solvents, 60 mg (15%) of the expected methyl ester were collected, which ester had the melting point 112°-3° C.
(b) Synthesis of 4- 3-(1-adamantyl)-4-(6-methoxyhexyloxy)phenylethynyl!benzoic acid
In a manner analogous to Example 8(b), from 170 mg (0.34 mmol) of the preceding methyl ester, 100 mg (61%) of 4- 3-(1-adamantyl)-4-(6-methoxyhexyloxy)phenylethynyl!benzoic acid were collected, which acid had the melting point 241°-2° C.
EXAMPLE 31
Preparation of 4- 3-(1-adamantyl)-4- 2-(4-morpholino)ethoxy!phenylethynyl!!benzoic acid
(a) Synthesis of methyl 4- 3-(1-adamantyl)-4- 2-(4-morpholino)ethoxy!phenylethynyl!!benzoate
In a manner analogous to Example 29(a), by reaction of 750 mg (1.9 mmol) of methyl 4- 3-(1-adamantyl)-4-hydroxyphenylethynyl!benzoate with 430 mg (2.3 mmol) of 4-(2-chloroethyl)morpholine hydrochloride, 540 mg (56%) of the expected methyl ester were obtained, which ester had the melting point 208°-9° C.
(b) Synthesis of 4- 3-(1-adamantyl)-4- 2-(4-morpholino)ethoxy!phenylethynyl!!benzoic acid
In a manner analogous to Example 8(b), from 540 mg (1 mmol) of the preceding methyl ester, 410 mg (79%) of 4- 3-(1-adamantyl)-4- 2-(4-morpholino)ethoxy!-phenylethynyl!benzoic acid were collected, which acid had the melting point 271°-2° C.
EXAMPLE 32
Preparation of 4- 3-(1-adamantyl)-4-(5-carbamoylpentyloxy)phenylethynyl!benzoic acid
(a) Synthesis of methyl 4- 3-(1-adamantyl)-4-(5-carbamoylpentyloxy)phenylethynyl!benzoate
In a manner analogous to Example 29(a), by reaction of 772 mg (2 mmol) of methyl 4- 3-(1-adamantyl)-4-hydroxyphenylethynyl!benzoate with 584 mg (3 mmol) of 6-bromohexanamide, 264 mg (26%) of the expected methyl ester were obtained, which ester had the melting point 198°-200° C.
(b) Synthesis of 4- 3-(1-adamantyl)-4-(5-carbamoylpentyloxy)phenylethynyl!benzoic acid
In a manner analogous to Example 8(b), from 254 mg (0.5 mmol) of the preceding methyl ester, 100 mg (40%) of 4- 3-(1-adamantyl)-4-(5-carbamoylpentyloxy)phenylethynyl!benzoic acid were collected, which acid had the melting point 269°-70° C.
EXAMPLE 33
Preparation of 4- 3-(1-adamantyl)-4-(3-hydroxypropyloxy)phenylethynyl!benzoic acid
(a) Synthesis of methyl 4- 3-(1-adamantyl)-4-(3-hydroxypropyloxy)phenylethynyl!benzoate
In a manner analogous to Example 29(a), by reaction of 773 mg (2 mmol) of methyl 4- 3-(1-adamantyl)-4-hydroxyphenylethynyl!benzoate with 417 mg (3 mmol) of 3-bromo-1-propanol, 683 mg (77%) of the expected methyl ester were obtained, which ester had the melting point 180°-2° C.
(b) Synthesis of 4- 3-(1-adamantyl)-4-(3-hydroxypropyloxy)phenylethynyl!benzoic acid
In a manner analogous to Example 8(b), from 678 mg (1.52 mmol) of the preceding methyl ester, 600 mg (92%) of 4- 3-(1-adamantyl)-4-(3-hydroxypropyloxy)phenylethynyl!benzoic acid were collected, which acid had the melting point 290°-2° C.
EXAMPLE 34
Preparation of 4- 3-(1-adamantyl)-4-(3-hydroxy-2-methylpropyloxy)phenylethynyl!benzoic acid
(a) Synthesis of methyl 4- 3-(1-adamantyl)-4-(3-hydroxy-2-methylpropyloxy)phenylethynyl!benzoate
In a manner analogous to Example 29(a), by reaction of 773 mg (2 mmol) of methyl 4- 3-(1-adamantyl)-4-hydroxyphenylethynyl!benzoate with 477 mg (3 mmol) of 3-bromo-2-methyl-1-propanol, 250 mg (27%) of the expected methyl ester were obtained, which ester had the melting point 174°-6° C.
(b) Synthesis of 4- 3-(1-adamantyl)-4-(3-hydroxy-2-methylpropyloxy)phenylethynyl!benzoic acid
In a manner analogous to Example 8(b), from 228 mg (0.5 mmol) of the preceding methyl ester, 166 mg (72%) of 4- 3-(1-adamantyl)-4-(3-hydroxy-2-methylpropyloxy)phenylethynyl!benzoic acid were collected, which acid had the melting point 260°-2° C.
EXAMPLE 35
Preparation of 4- 3-(1-adamantyl)-4- (2,2-dimethyl-1,3-dioxolan-4-methoxy)phenylethynyl!benzoic acid
(a) Synthesis of methyl 4- 3-(1-adamantyl)-4- (2,2-dimethyl-1,3-dioxolan-4-methoxy)phenylethynyl!benzoate
1.22 g (3.1 mmol) of methyl 4- 3-(1-adamantyl)-4-hydroxyphenylethynyl!benzoate in 25 ml of DMF was treated successively with 523 mg of potassium carbonate and 1.08 g (3.8 mmol) of 3-tosyloxy-1,2-propanediol acetonide. The reaction mixture was stirred at room temperature for four hours and then heated at 80° C. for sixteen hours.
After the usual treatment, the residue obtained was triturated in heptane, filtered and dried. 862 mg (55%) of the expected methyl ester were collected, which ester had the melting point 203°-4° C.
(b) Synthesis of 4- 3-(1-adamantyl)-4- (2,2-dimethyl-1,3-dioxolan-4-methoxy)phenylethynyl!benzoic acid
In a manner analogous to Example 8(b), from 404 mg (0.8 mmol) of the preceding methyl ester, 341 mg (87%) of 4- 3-(1-adamantyl)-4- (2,2-dimethyl-1,3-dioxolan-4-methoxy)phenylethynyl!benzoic acid were collected, which acid had the melting point 272°-4° C.
EXAMPLE 36
Preparation of 4- 3-(1-adamantyl)-4-(2,3-dihydroxypropyloxy)phenylethynyl!benzoic acid
(a) Synthesis of methyl 4- 3-(1-adamantyl)-4-(2,3-dihydroxypropyloxy)phenylethynyl!benzoate
450 mg (0.9 mmol) of methyl 4- 3-(1-adamantyl)-4- (2,2-dimethyl-1,3-dioxolan-4-yl)methoxy!phenyl-ethynyl!benzoate were placed in suspension in 10 ml of a formic acid solution (40%) and heated at 100° C. for three days. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulphate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with dichloromethane. 220 mg (53%) of the expected methyl ester were collected, which ester had the melting point 202°-3° C.
(b) Synthesis of 4- 3-(1-adamantyl)-4-(2,3-dihydroxypropyloxy)phenylethynyl!benzoic acid
In a manner analogous to Example 8(b), from 205 mg (0.44 mmol) of the preceding methyl ester, 153 mg (78%) of 4- 3-(1-adamantyl)-4-(2,3-dihydroxypropyloxy)phenylethynylbenzoic acid were collected, which acid had the melting point 300°-2° C.
EXAMPLE 37
In this example, various specific formulations based on the compounds according to the invention are illustrated.
(A) ORAL ROUTE
(a) 0.2 g Tablet
______________________________________                                    
(i)     Compound prepared in Example 1                                    
                              0.001 g                                     
(ii)    Starch                0.114 g                                     
(iii)   Dicalcium phosphate   0.020 g                                     
(iv)    Silica                0.020 g                                     
(v)     Lactose               0.030 g                                     
(vi)    Talc                  0.010 g                                     
(vi)    Magnesium stearate    0.005 g                                     
______________________________________
(b) Oral (drinkable) suspension in 10 ml ampoules
______________________________________                                    
(i)     Compound of Example 2 0.05 g                                      
(ii)    Glycerol              1.000 g                                     
(iii)   70% Sorbitol          1.000 g                                     
(iv)    Sodium saccharin      0.010 g                                     
(v)     Methyl para-hydroxybenzoate                                       
                              0.080 g                                     
(vi)    Flavoring q.s.        0.080 g                                     
(vii)   Purified water q.s. for                                           
                              10 mil                                      
______________________________________
(B) TOPICAL ROUTE
(a) Ointment
______________________________________                                    
(i)      Compound of Example 1                                            
                             0.020 g                                      
(ii)     Isopropyl myristate                                              
                            81.700 g                                      
(iii)    Fluid paraffin oil  9.100 g                                      
(iv)     Silica ("Aerosil 200"                                            
                             9.180 g                                      
         marketed by Degussa)                                             
______________________________________
(b) Ointment
______________________________________                                    
(i)     Compound of Example 2                                             
                            0.300  g                                      
(ii)    Pharmaceutical-grade white                                        
                            100    g                                      
        petroleum jelly q.s. for                                          
______________________________________
(c) Nonionic water-in-oil cream
______________________________________                                    
(i)    Compound of Example 3  0.100   g                                   
(ii)   Mixture of emulsified lanolin alcohols,                            
                              39.900  g                                   
       waxes and oils ("Anhydrous Eucerin"                                
       marketed by BDF)                                                   
(iii)  Methyl para-hydroxybenzoate                                        
                              0.075   g                                   
(iv)   Propyl para-hydroxybenzoate                                        
                              0.075   g                                   
(v)    Sterile demineralized water q.s. for                               
                              100     g                                   
______________________________________
(d) Lotion
______________________________________                                    
(i)     Compound of Example 1                                             
                              0.100 g                                     
(ii)    Polyethylene glycol (PEG 400)                                     
                             69.900 g                                     
(iii)   95% Ethanol          30.000 g                                     
______________________________________
(e) Hydrophobic ointment
______________________________________                                    
(i)    Compound of Example 3 0.300   g                                    
(ii)   Isopropyl myristate   36.400  g                                    
(iii)  Silicone oil ("Rhodorsil 47 V 300"                                 
                             36.400  g                                    
       marketed by Rhone-Poulenc)                                         
(iv)   Beeswax               13.600  g                                    
(v)    Silicone oil ("Abil 300.000 cst"                                   
                             100     g                                    
       marketed by Goldschmidt) q.s. for                                  
______________________________________
(f) Nonionic oil-in-water cream
______________________________________                                    
(i)    Compound of Example 4 0.500  g                                     
(ii)   Cetyl alcohol         4.000  g                                     
(iii)  Glyceryl monostearate 2.500  g                                     
(iv)   PEG 50 stearate       2.500  g                                     
(v)    Karite butter         9.200  g                                     
(vi)   Propylene glycol      2.000  g                                     
(vi)   Methyl para-hydroxybenzoate                                        
                             0.075  g                                     
(viii) Propyl para-hydroxybenzoate                                        
                             0.075  g                                     
(ix)   Sterile demineralized water q.s. for                               
                             100    g                                     
______________________________________
While the invention has been described in terms of various preferred embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the following claims, including equivalents thereof.

Claims (24)

What is claimed is:
1. A method for treating a skin or hair disorder on a mammalian organism in need of such treatment, comprising administering to such organism a cosmetically/therapeutically effective amount of a cosmetic/therapeutic composition comprising a cosmetically or therapeutically effective amount of an adamantyl-substituted polycyclic acetylene compound having the structural formula (I) an adamantyl-substituted polycyclic acetylene compound having the structural formula (I): ##STR7## in which X represents a hydrogen atom or a halogen atom; R1 represents a hydrogen atom, a --CH3 radical, a --CH2 --O--R4 radical, a --CH2 --O--CO--R5 radical, an --O--R6 radical, an --O--(CH2)m --(CO)n --R7 radical, a --(CH2)p --CO--R8 radical, a --(CH2)p --CO--O--R9 radical or an --S(O)p --R10 radical, wherein the m, n and p and the radicals R4 to R10 are defined below; Ar is a radical selected from among those of the following radicals of formulae (a)-(f): ##STR8## wherein R10 and R11 are as defined below; R2 is a hydrogen atom or a halogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, an --O--CH2 --O--CH2 --CH2 --O--CH3 radical or an --O--R13 radical, wherein R13 is as defined below; R3 is an --O--CH2 --O--CH2 --CH2 --O--CH3 radical, a --(Y)n --(CH2)q --R14 radical, a --(CH2)m --Y--(CH2)q --R14 radical or a --CH═CH--(CH2)t --R14, radical, wherein m, n, q and t and the Y and R14 radicals are as defined below; m, is an integer equal to 1, 2 or 3, n, is an integer equal to 0 or 1, p is an integer equal to 0, 1, 2 or 3, q is an integer ranging from 0 and 12, inclusive, and t is an integer ranging from 0 to 10, inclusive, R4 is a hydrogen atom or a lower alkyl radical; R5 is a lower alkyl radical; R6 is a hydrogen atom or a lower alkyl radical; R7 is a lower alkyl radical or a radical: ##STR9## in which R' and R", identical or different, are each a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino acid or peptide or sugar residue, with the proviso that R' and R" may together form, with the nitrogen atom from which they depend, a nitrogen-containing heterocycle; R9 is a hydrogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, an alkenyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl or aralkyl radical, or a sugar residue or an amino acid or peptide residue, R10 is a hydrogen atom or a lower alkyl radical; R11 is a hydrogen atom, a halogen atom, a lower alkyl radical, a hydroxyl radical, or an --O--R12 or --O--COR12 radical, R12 is as defined below; R12 is as a lower alkyl radical; R13 is a hydrogen atom or a linear or branched alkyl radical having from 1 to 20 carbon atoms; R14 is a hydrogen atom, a lower alkyl radical, an alkenyl radical, an alkynyl radical, a C3 -C6 cycloaliphatic radical, a mono- or polyhydroxyalkyl radical, said hydroxyls are optionally being protected as methoxy, acetoxy or acetonide groups, an aryl or aralkyl radical, a --CO--R8 radical, a --COOR9 radical, an --S(O)p --R10 radical, a radical: ##STR10## or, but only in the event that n is equal to 0 and R3 is -- (Y)n-- (CH2)q-- R14, a hydroxyl radical, an --O--R12 radical or an --O--COR12 radical, Y is an oxygen or sulphur atom or an --S(O)p radical; or a pharmaceutically/cosmetically acceptable salt or optical or geometric isomer thereof.
2. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of Formula (I), Ar has the structure (a).
3. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of Formula (I), Ar has the structure (b).
4. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of Formula (I), Ar has the structure (c).
5. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of Formula (I), Ar has the structure (d).
6. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of Formula (I), Ar has the structure (e).
7. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of Formula (I), Ar has the structure (f).
8. The method of claim 1, wherein said adamantyl-substituted polycyclic acetylene compound comprises a pharmaceutically acceptable salt of the compound having structural formula (I).
9. The method of claim 1, where in said adamantyl-substituted polycyclic acetylene compound of Formula (I), the lower alkyl substituents are selected from the group consisting of methyl, ethyl, isopropyl, butyl, tert.-butyl and hexyl radicals.
10. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of formula (I), the linear or branched alkyl radical substituents having from 1 to 20 carbon atoms are selected from the group consisting of methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl radicals.
11. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of formula (I), the monohydroxyalkyl radical substituents are selected from the group consisting of 2-hydroxypropyl and 3-hydroxypropyl radicals.
12. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of formula (I), the polyhydroxyalkyl radical substituents are selected from the group consisting of 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl and pentaerythritol radicals.
13. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of formula (I), the aryl radical substituents are selected from the group consisting of phenyl radicals optionally substituted by at least one halogen atom, a hydroxyl and a nitro functional group.
14. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of formula (I), the aralkyl radical substituents are selected from the group consisting of benzyl and phenethyl radicals optionally substituted by at least one halogen atom, or a hydroxyl or nitro functional group.
15. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of formula (I), the alkenyl radical substituents have from 2 to 5 carbon atoms and have at least one site of ethylenic unsaturation.
16. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of formula (I), the alkynyl radical substituents have from 2 to 6 carbon atoms.
17. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of formula (I), the sugar residue substituents are selected from the group consisting of glucose, galactose, mannose and glucuronic acid.
18. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of formula (I), the amino acid residue substituents are selected from the group consisting of lysine, glycine and aspartic acid.
19. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of formula (I), the peptide residue substituents are those of a dipeptide or tripeptide.
20. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of formula (I), the heterocyclic radical substituents are selected from the group consisting of piperidino, morpholino, pyrrolidino and piperazino radicals which are optionally substituted by a C1 -C6 alkyl radical or a mono- or polyhydroxyalkyl radical.
21. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of formula (I), the halogen atom substituents are selected from the group consisting of fluorine, chlorine and bromine atoms.
22. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound is selected from the group consisting of
4- 3-(1-Adamantyl)-4-methoxyphenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!-benzoic acid
4- 3-(1-Adamantyl)-4-hydroxyphenylethynyl!benzoic acid
5- 3-(1-Adamantyl)-4-methoxyphenylethynyl!-2-thiophenecarboxylic acid
5- 3-(1-Adamantyl)-4-hydroxyphenylethynyl!-2-thiophenecarboxylic acid
2- 3-(1-Adamantyl)-4-methoxyphenylethynyl!-4-thiophenecarboxylic acid
6- 3-(1-Adamantyl)-4-methoxyphenylethynyl!-2-naphthoic acid
4- 3-(1-Adamantyl)-4-nonyloxyphenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-hexyloxyphenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-dodecyloxyphenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-cyclopropylmethoxyphenylethynyl!benzoic acid
4- 2-Hexyloxy-5-(1-adamantyl)-4-hexyloxyphenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-heptyloxyphenylethynyl!benzoic acid
6- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!-nicotinic acid
4- 2-Methoxy-5-(1-adamantyl)-4-methoxyphenylethynyl!benzoic acid
4- 2-Methoxyethoxymethoxy-5-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoic acid
4- 2-Methoxy-5-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-benzyloxyphenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!-benzaldehyde
4- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!-benzenemethanol
4- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!-benzyl acetate
4- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!-phenyl acetate
4- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!-phenol
4- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!-phenoxyethylmorpho-line
4- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzamide
N-Ethyl-4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzamide
4- 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoic acid morpholide
2-Hydroxy-4- 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-(6-hydroxyhexyloxy)phenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-(6-methoxyhexyloxy)phenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4- 2-(4-morpholino)-ethoxy!phenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-(6-carbamoylpropyloxy)phenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-(5-carbamoylpentyloxy)phenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-(3-hydroxypropyloxy)phenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-(3-hydroxy-2-methylpropyloxy)phenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4- (2,2-dimethyl-1,3-dioxolan-4-yl)methoxy!phenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-(2,3-dihydroxypropyloxy)phenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-methoxyethoxyethylphenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-methoxymethoxypropylphenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-methoxyethoxypropylphenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-acetoxybutoxyphenylethynyl!benzoic acid
4- 3-(1-Adamantyl)-4-acetoxypropyloxyphenylethynyl!benzoic acid.
23. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound is an alkali or alkaline earth metal, zinc or amine salt.
24. The method of claim 1, where in the adamantyl-substituted polycyclic acetylene compound of formula (I), at least one R1, R2, R3 or Ar must be defined as set forth below:
R1 is a --(CH2)p --CO--R8 radical;
R3 is an --O--CH2 --O--CH2 --CH2 --O--CH3 or ----(--Y--)----n ----(--CH2 --)----q --R14 radical;
Ar is a radical selected from among those of formulae (a) and (e); and
R2 is a linear or branched alkyl radical having from 1 to 20 carbon atoms or an --O--R13 radical.
US08/678,416 1994-04-26 1996-07-02 Use of adamantyl-substituted polycyclic acetylene compounds in skin and hair treatment Expired - Fee Related US5798354A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US08/678,416 US5798354A (en) 1994-04-26 1996-07-02 Use of adamantyl-substituted polycyclic acetylene compounds in skin and hair treatment

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
FR9405018A FR2719044B1 (en) 1994-04-26 1994-04-26 New acetylenated bi-aromatic compounds with adamantyl group, pharmaceutical and cosmetic compositions containing them and uses.
FR9405018 1994-04-26
US08/429,045 US5574036A (en) 1994-04-26 1995-04-26 Adamantyl-substituted polycyclic acetylene compounds and pharmaceutical/cosmetic compositions comprised thereof
US08/678,416 US5798354A (en) 1994-04-26 1996-07-02 Use of adamantyl-substituted polycyclic acetylene compounds in skin and hair treatment

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US08/429,045 Division US5574036A (en) 1994-04-26 1995-04-26 Adamantyl-substituted polycyclic acetylene compounds and pharmaceutical/cosmetic compositions comprised thereof

Publications (1)

Publication Number Publication Date
US5798354A true US5798354A (en) 1998-08-25

Family

ID=9462511

Family Applications (2)

Application Number Title Priority Date Filing Date
US08/429,045 Expired - Fee Related US5574036A (en) 1994-04-26 1995-04-26 Adamantyl-substituted polycyclic acetylene compounds and pharmaceutical/cosmetic compositions comprised thereof
US08/678,416 Expired - Fee Related US5798354A (en) 1994-04-26 1996-07-02 Use of adamantyl-substituted polycyclic acetylene compounds in skin and hair treatment

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US08/429,045 Expired - Fee Related US5574036A (en) 1994-04-26 1995-04-26 Adamantyl-substituted polycyclic acetylene compounds and pharmaceutical/cosmetic compositions comprised thereof

Country Status (20)

Country Link
US (2) US5574036A (en)
EP (1) EP0679631B1 (en)
JP (1) JP2756424B2 (en)
KR (1) KR100191819B1 (en)
AT (1) ATE165808T1 (en)
AU (1) AU674814B2 (en)
BR (1) BR9501613A (en)
CA (1) CA2147808C (en)
DE (1) DE69502334T2 (en)
DK (1) DK0679631T3 (en)
ES (1) ES2120145T3 (en)
FI (1) FI951983A (en)
FR (1) FR2719044B1 (en)
HU (1) HU217832B (en)
IL (1) IL113474A (en)
NO (1) NO303492B1 (en)
NZ (1) NZ270914A (en)
PL (1) PL180846B1 (en)
RU (1) RU2125554C1 (en)
ZA (1) ZA952975B (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001003659A1 (en) * 1999-07-13 2001-01-18 The Salk Institute For Biological Studies Use of rar antagonists as modulators of hormone mediated processes
US6248749B1 (en) * 1996-10-31 2001-06-19 Centre International De Recherches Dermatologiques Galderma Use of inhibitors of the activity of retinoic acid for treating sensit ive skin and/or acute damage induced by UV radiation
WO2010043000A1 (en) * 2008-10-17 2010-04-22 Akaal Pharma Pty Ltd S1p receptors modulators and their use thereof
US9181182B2 (en) 2008-10-17 2015-11-10 Akaal Pharma Pty Ltd S1P receptors modulators

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2733684B1 (en) * 1995-05-03 1997-05-30 Cird Galderma USE OF RETINOIDS IN A COSMETIC COMPOSITION OR FOR THE MANUFACTURE OF A PHARMACEUTICAL COMPOSITION
FR2741878B1 (en) * 1995-12-01 1998-01-09 Cird Galderma BIAROMATIC COMPOUNDS CARRYING AN ADAMANTYL ORTHO GROUP, PHARMACEUTICAL AND COSMETIC COMPOSITIONS CONTAINING THEM AND USES THEREOF
FR2757852B1 (en) * 1996-12-31 1999-02-19 Cird Galderma STILBENIC COMPOUNDS WITH ADAMANTYL GROUP, COMPOSITIONS CONTAINING SAME, AND USES
FR2763588B1 (en) * 1997-05-23 1999-07-09 Cird Galderma TRIAROMATIC COMPOUNDS, COMPOSITIONS CONTAINING THEM, AND USES
US6262117B1 (en) 1999-02-18 2001-07-17 Allergan Sales, Inc. Method and composition for treating acne
US6711552B1 (en) * 1999-08-27 2004-03-23 Matthew W. Kay Apparatus and method for saving commerce related information in a broadcast programming network
US6956049B1 (en) * 1999-08-31 2005-10-18 Merck & Co., Inc. Methods of modulating processes mediated by excitatory amino acid receptors
FR2804323B1 (en) * 2000-01-31 2006-07-07 Galderma Res & Dev USE OF RETINOID-LIKE COMPOUNDS AS ANTI-BACTERIAL AGENTS
GB0103045D0 (en) * 2001-02-07 2001-03-21 Novartis Ag Organic Compounds
AU2003285957A1 (en) * 2002-10-24 2004-05-13 Merck & Co., Inc. Alkyne derivatives as tracers for metabotropic glutamate receptor binding
JP4736463B2 (en) * 2004-02-27 2011-07-27 住友ベークライト株式会社 Condensed polymer raw materials and their synthesis
JP2007031663A (en) * 2005-07-29 2007-02-08 Fujifilm Corp Film-forming composition and insulating film and electron device formed by using the same
FR2910320B1 (en) 2006-12-21 2009-02-13 Galderma Res & Dev S N C Snc EMULSION COMPRISING AT LEAST ONE RETINOID AND BENZOLE PEROXIDE
FR2910321B1 (en) 2006-12-21 2009-07-10 Galderma Res & Dev S N C Snc CREAM GEL COMPRISING AT LEAST ONE RETINOID AND BENZOLE PEROXIDE
FR2931661B1 (en) 2008-05-30 2010-07-30 Galderma Res & Dev NOVEL DEPIGMENTING COMPOSITIONS IN THE FORM OF AN ANHYDROUS VASELIN - FREE AND ELASTOMER - FREE COMPOSITION COMPRISING A SOLUBILIZED PHENOLIC DERIVATIVE AND A RETINOID.

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0176034B1 (en) * 1984-09-22 1989-08-30 BASF Aktiengesellschaft Diaryl acetylenes, their preparation and use

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0176034B1 (en) * 1984-09-22 1989-08-30 BASF Aktiengesellschaft Diaryl acetylenes, their preparation and use

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, vol. 87, No. 3, Jul. 18, 1977, Columbus, Ohio; abstract No. 22693b, Musantaeva, Sh. et al, "Synthesis of P-Acetylenylbenzoic Acid", p. 599, Col. 2; & Deposited Doc., 1974, pp. 297-375, VINTI.
Chemical Abstracts, vol. 87, No. 3, Jul. 18, 1977, Columbus, Ohio; abstract No. 22693b, Musantaeva, Sh. et al, Synthesis of P Acetylenylbenzoic Acid , p. 599, Col. 2; & Deposited Doc., 1974, pp. 297 375, VINTI. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6248749B1 (en) * 1996-10-31 2001-06-19 Centre International De Recherches Dermatologiques Galderma Use of inhibitors of the activity of retinoic acid for treating sensit ive skin and/or acute damage induced by UV radiation
WO2001003659A1 (en) * 1999-07-13 2001-01-18 The Salk Institute For Biological Studies Use of rar antagonists as modulators of hormone mediated processes
US6436993B1 (en) * 1999-07-13 2002-08-20 The Salk Institute For Biological Studies Use of RAR antagonists as modulators of hormone mediated processes
WO2010043000A1 (en) * 2008-10-17 2010-04-22 Akaal Pharma Pty Ltd S1p receptors modulators and their use thereof
US8592399B2 (en) 2008-10-17 2013-11-26 Akaal Pharma Pty Ltd. S1P receptors modulators and their use thereof
US9181182B2 (en) 2008-10-17 2015-11-10 Akaal Pharma Pty Ltd S1P receptors modulators
US9193716B2 (en) 2008-10-17 2015-11-24 Akaal Pharma Pty Ltd. S1P receptors modulators and their use thereof
US9707205B2 (en) 2008-10-17 2017-07-18 Akaal Pharma Pty Ltd. S1P receptors modulators and their use thereof

Also Published As

Publication number Publication date
IL113474A (en) 2000-06-01
IL113474A0 (en) 1995-07-31
DK0679631T3 (en) 1998-10-07
FR2719044A1 (en) 1995-10-27
HU217832B (en) 2000-04-28
RU2125554C1 (en) 1999-01-27
ATE165808T1 (en) 1998-05-15
NZ270914A (en) 1997-01-29
FI951983A (en) 1995-10-27
NO303492B1 (en) 1998-07-20
PL180846B1 (en) 2001-04-30
AU1650995A (en) 1995-11-16
NO951544L (en) 1995-10-27
HU9501166D0 (en) 1995-06-28
DE69502334D1 (en) 1998-06-10
ES2120145T3 (en) 1998-10-16
EP0679631B1 (en) 1998-05-06
PL308339A1 (en) 1995-10-30
BR9501613A (en) 1997-09-16
KR100191819B1 (en) 1999-06-15
JPH0892136A (en) 1996-04-09
EP0679631A1 (en) 1995-11-02
DE69502334T2 (en) 1998-09-03
RU95106684A (en) 1996-12-27
ZA952975B (en) 1995-12-21
AU674814B2 (en) 1997-01-09
HUT74009A (en) 1996-10-28
US5574036A (en) 1996-11-12
CA2147808A1 (en) 1995-10-27
CA2147808C (en) 2001-02-13
FR2719044B1 (en) 1996-05-31
JP2756424B2 (en) 1998-05-25
FI951983A0 (en) 1995-04-26
NO951544D0 (en) 1995-04-24

Similar Documents

Publication Publication Date Title
US5786379A (en) Adamantyl-substituted biaromatic compounds and pharmaceutical/cosmetic compositions comprised thereof
US4927928A (en) Aromatic benzamido compounds, their preparation and their use in human or veterinary medicine or in cosmetic preparations
US4925658A (en) Aromatic esters and thioesters and their use in human or veterinary medicine and in cosmetic compositions
US6368608B1 (en) Polyaromatic propynyl compounds and pharmaceutical/cosmetic compositions comprised thereof
US5798354A (en) Use of adamantyl-substituted polycyclic acetylene compounds in skin and hair treatment
US5952382A (en) Adamantyl-substituted retinoids and pharmaceutical/cosmetic compositions comprised thereof
US5387594A (en) Di(aromatic) compounds and their use in human and veterinary medicine and in cosmetics
US6992095B2 (en) Stilbene compounds comprising an adamantyl group, compositions and methods thereof
US5705167A (en) Aromatic polyenic compounds and pharmaceutical/cosmetic compositions comprised thereof
US5547983A (en) Aromatic and polycyclic compounds and their use in human or veterinary medicine and in cosmetics
US5877342A (en) Adamantyl-substituted biaromatic compounds and pharmaceutical/cosmetic compositions comprised thereof
US6515021B1 (en) Bicyclic aromatic compounds
US5763487A (en) Bioactive bicyclic aromatic compounds and pharmaceutical/cosmetic compositions comprised thereof
US5766610A (en) Polycyclic aromatic compounds and pharmaceutical/cosmetic compositions comprised thereof
US6051243A (en) Polyaromatic amide compounds and pharmaceutical/cosmetic compositions comprised thereof
US5476860A (en) Diaromatic compounds derived from a salicylic unit and their use in human and veterinary medicine and in cosmetics
US5702710A (en) Dibenzofuran compounds and pharmaceutical/cosmetic compositions comprised thereof
US5723499A (en) Polycyclic aromatic compounds and pharmaceutical/cosmetic compositions comprised thereof
US5935585A (en) Biaromatic amido compounds and pharmaceutical/cosmetic compositions comprised thereof
EA001060B1 (en) Diaromatic propynyl or dienyl compounds, intermediate compounds of pharmacological and cosmetic compositions and usage of cosmetic compositions
US20030216586A1 (en) Biaromatic compounds and pharmaceutical and cosmetic compositions comprising them
US5468897A (en) Bi-aromatic esters, a process for their preparation and their use in human or veterinary medicine and in cosmetic compositions
US5212203A (en) Aromatic benzamido compounds; their preparation and their use in human or veterinary medicine or in cosmetic preparations
US6162815A (en) RXR-agonist polycyclic aromatic compounds, pharmaceutical/cosmetic compositions comprising said compound and uses thereof
US6057341A (en) Bi-aromatic dibenzofuran derivatives and their use in human and veterinary medicine and in cosmetics

Legal Events

Date Code Title Description
CC Certificate of correction
FPAY Fee payment

Year of fee payment: 4

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20060825